CN108473489A - VALBENAZINE salt and its polymorph - Google Patents

VALBENAZINE salt and its polymorph Download PDF

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Publication number
CN108473489A
CN108473489A CN201680072826.6A CN201680072826A CN108473489A CN 108473489 A CN108473489 A CN 108473489A CN 201680072826 A CN201680072826 A CN 201680072826A CN 108473489 A CN108473489 A CN 108473489A
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CN108473489B (en
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凯文·麦吉
斯科特·朱克
安德鲁·卡尔
希尔瑞·伯诺德
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Neurocrine Biosciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

There is provided herein amorphous and crystal form 3 methylbutanoic acid (2R of (S) 2 amino, 3R, 11bR) 3 isobutyl group, 9,10 dimethoxy 1,3,4,6,7,11b hexahydro 2H pyridos [2, l a] isoquinolin 2 base ester salt and preparation method and its pharmaceutical composition.Additionally provide they for treat, prevent or improve neuropathic conditions and disease (including hyperkinesia dyskinesia or disease) one or more symptoms method.

Description

VALBENAZINE salt and its polymorph
Cross reference to related applications
This application claims the equity for No. 62/249,074 U.S. Provisional Application that on October 30th, 2015 submits；Its disclosure Content is incorporated herein by reference in their entirety.
Field
There is provided herein amorphous and crystal form (S) -2- amino -3- metliyl-butyric acids (2R, 3R, 11bR) -3- isobutyls It is prepared by base -9,10- dimethoxy -1,3, the salt of 4,6,7,11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl esters Method and its pharmaceutical composition.Them are additionally provided for treating, preventing or improving neuropathic conditions and disease (including fitness machine Can hyperfunction property dyskinesia or disease) one or more symptoms method.
Background
Hyperkinesia venereal disease disease is characterized by excessive, abnormal involuntary movement.These neuropathic conditions include Tremble, dystonia, ballism, twitch, cathisophobia, stereotypy, chorea, myoclonia and athetosis.Although less managing Solve the Pathological Physiology of these movement disorders, but it is believed that, the dysregulation of the neurotransmitter in basal ganglion rises important It acts on (Kenney et al., Expert Review Neurotherapeutics, 2005,6,7-17).Typical neuroleptic drug Or the antiemetic of the blocking dopamine receptor of central action long-time service and high dose so that patient is susceptible to suffer from Delayed onset syndrome Breaking-out.Tardive dyskinesia (a kind of hypotype of posterior syndrome) with face, four limbs or trunk it is quick, repeating, Mechanical, involuntary movement is characterized (Muller, Expert Opin.Investig.Drugs, 2015,24,737-742).
3- isobutyl groups -9,10- dimethoxys -1,3,4,6,7,11b- hexahydro -2H- pyridos [2, l-a] isoquinolin -2- ketone (also referred to as tetrabenazine (TBZ)) can improve various fortune to the reversible inhibition of -2 system of vesicular monoamine transporters (VMAT2) The treatment of dynamic hyperfunction dyskinesia.However, the shortcomings that such treatment be fluctuation response, due to TBZ tachymetabolisms and To the needs frequently taken in and side effect.Side effect related with TBZ includes calmness, depression, cathisophobias and Parkinson Disease.
TBZ (it contains 2 chiral centres and is the racemic mixture of two kinds of stereoisomers) in vivo rapidly and Widely it is metabolized to its reduction form, 3- isobutyl group -9,10- dimethoxys -1,3,4,6,7,11b- hexahydro -2H- pyridos [2, l-a] isoquinolin -2- alcohol, also referred to as dihydrotetrabenazinein (DHTBZ).DHTBZ is considered as four kinds of individual isomers In the presence of：(±) α-DHTBZ and (±) β-DHTBZ.2R, 3R, 11bR or (+) α-DHTBZ are considered as the absolute of active metabolite Configuration (Kilbourn et al., Chirality, 1997,9,59-62).Tetrabenazine the U.S. have Orphan drug status, and Certain European countries go through.Its application is also allowed for the choreic treatment in the patient with Huntington's disease.So And tetrabenazine is rapidly metabolized, and (Muller, Expert must be frequently applied in one day Opin.Investig.Drugs,2015,24,737-742).Therefore, there is unmet split hair in the art In the needs of effective therapeutic agent for the treatment of hyperkinesia dyskinesia (including tardive dyskinesia).
Valbenazine, (S) -2- amino -3- metliyl-butyric acids (2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxies Base -1,3,4,6,7,11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl esters, purified dihydrotetrabenazinein The prodrug of (+)-alpha-isomer is shown recently to hyperkinesia dyskinesia (including tardive dyskinesia symptom) The unique for the treatment of improve, there are improved pharmacokinetics and tolerance characteristics.
Disclosure is summarized
There is provided herein (S) -2- amino -3- metliyl-butyric acids (2R, 3R, 11bR) -3- isobutyl group -9,10- diformazans of following formula Oxy-1, the pharmaceutically acceptable salt of 3,4,6,7,11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl ester：
Or its isotopic variations；Or its solvate.
There is provided herein the 2- of the Formulas I of crystal form amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups - Two (4- toluenesulfonic acids of 9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Salt)：
Or its isotopic variations；Or its solvate.
2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR)-of form I, II, III, IV, V and VI is also provided herein Two (4- of 3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Toluenesulfonate) (Formulas I) or its isotopic variations or its solvate.
There is provided herein 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, the 11bR) -3- isobutyls for being used to prepare crystal form Two (4- methylbenzenes of base -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Sulfonate) (Formulas I) or its isotopic variations；Or the method for its pharmaceutically acceptable salt or solvate, the method includes In the first temperature by 2- amino -3 Methylbutanoic acid (S)-dimethoxy -2,3,4,6 (2R, 3R, 11bR) -3- isobutyl group -9,10-, 7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) dissolve in a solvent.
There is provided herein pharmaceutical composition, it includes the 2- of crystal form amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester Two (4- toluenesulfonates) (Formulas I) or its isotopic variations；Or its solvate.
There is provided herein the sides of one or more symptoms for treating, preventing or improving hyperkinesia venereal disease disease Method, the method includes giving individual application (S) -2- amino -3- metliyl-butyric acid (2R, 3R, 11bR) -3- isobutyl groups -9,10- bis- The pharmaceutically acceptable salt of methoxyl group -1,3,4,6,7,11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl ester or its Isotopic variations；Or its solvate.
There is provided herein the sides of one or more symptoms for treating, preventing or improving hyperkinesia venereal disease disease Method, the method includes 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyls of crystal form are applied to individual Two (4- methylbenzenes of base -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Sulfonate) (Formulas I) or its isotopic variations；Or its solvate.
Brief Description Of Drawings
Fig. 1 is depicted at 2- amino -3 Methylbutanoic acid (S)-isobutyl group -9 (2R, 3R, 11bR) -3- of crystal form I, Two (4- toluenesulfonic acids of 10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Salt) (Formulas I) sample exemplary X-ray powder (XRP) diffraction pattern.
Exemplary hot gravimetry (TGA) thermogram that Fig. 2 is depicted at the sample of the Formulas I of crystal form I is (empty Line) and differential scanning calorimetry (DSC) diffraction pattern (solid line).
Fig. 3 is depicted at the example weight analysis vapor absorption (GVS) of the sample of the Formulas I of crystal form I.
Fig. 4 is depicted at scanning electron microscope (SEM) photo of the particle of the Formulas I sample of form I, and magnifying power is 500(A)；2,000(B)；With 5,000 (C).
Fig. 5 is depicted at exemplary X-ray powder (XRP) diffraction pattern of the sample of the Formulas I of crystalline Formula II.
Fig. 6 is depicted at exemplary differential scanning calorimetry (DSC) diffraction pattern of the sample of the Formulas I of crystalline Formula II (above) and thermogravimetry (TGA) thermogram (figure below).
Fig. 7 is depicted at the example weight analysis vapor absorption (GVS) of the sample of the Formulas I of crystalline Formula II.
Fig. 8 is depicted at exemplary X-ray powder (XRP) diffraction pattern of the sample of the Formulas I of crystalline formula III.
Fig. 9 is depicted at exemplary hot gravimetry (TGA) thermogram of the sample of the Formulas I of crystalline formula III (above) and differential scanning calorimetry (DSC) diffraction pattern (figure below).
Figure 10 is depicted at exemplary X-ray powder (XRP) diffraction pattern of the sample of the Formulas I of crystalline formula IV.
Figure 11 is depicted at exemplary hot gravimetry (TGA) thermogram of the sample of the Formulas I of crystalline formula IV (dotted line) and differential scanning calorimetry (DSC) diffraction pattern (solid line).
Figure 12 is depicted at the example weight analysis vapor absorption (GVS) of the sample of the Formulas I of crystalline formula IV.
Figure 13 is depicted at exemplary X-ray powder (XRP) diffraction pattern of the sample of the Formulas I of crystal form V.
Figure 14 is depicted at exemplary hot gravimetry (TGA) thermogram of the sample of the Formulas I of crystal form V (dotted line) and differential scanning calorimetry (DSC) diffraction pattern (solid line).
Figure 15 is depicted at the example weight analysis vapor absorption (GVS) of the sample of the Formulas I of crystal form V.
Figure 16 is depicted at exemplary X-ray powder (XRP) diffraction pattern of the sample of the Formulas I of crystalline Formula IV.
Figure 17 is depicted at exemplary hot gravimetry (TGA) thermogram of the sample of the Formulas I of crystalline Formula IV (solid line) and differential scanning calorimetry (DSC) diffraction pattern (dotted line).
Figure 18 is depicted at the example weight analysis vapor absorption (GVS) of the sample of the Formulas I of crystalline Formula IV.
Figure 19 is depicted at exemplary X-ray powder (XRP) diffraction pattern of the sample of the Formulas I of amorphous form.
Figure 20 is depicted at 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups-of crystal form I 9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochloride (Formula II) Sample exemplary X-ray powder (XRP) diffraction pattern.
Figure 21 is depicted at exemplary differential scanning calorimetry (DSC) diffraction pattern of the sample of the Formula II of crystal form I (above) and thermogravimetry (TGA) thermogram (figure below).
Figure 22 is depicted at the example weight analysis vapor absorption (GVS) of the sample of the Formula II of crystal form I.
Figure 23 is depicted at exemplary X-ray powder (XRP) diffraction pattern of the sample of the Formula II of crystalline Formula II.
Figure 24 is depicted at exemplary differential scanning calorimetry (DSC) diffraction pattern of the sample of the Formula II of crystalline Formula II (above) and thermogravimetry (TGA) thermogram (figure below).
Figure 25 is depicted at the example weight analysis vapor absorption (GVS) of the sample of the Formula II of crystalline Formula II.
Figure 26 is depicted at exemplary X-ray powder (XRP) diffraction pattern of the sample of the Formula II of amorphous form.
Dotted line and solid line in figure are only used for the purpose of differentiation figure, and are not intended to refer to the intensity of signal.
Detailed description of the invention
Definition
Many terms are defined below in disclosure set forth herein for ease of understanding.
In general, nomenclature used herein and organic chemistry described herein, pharmaceutical chemistry and pharmacological laboratory behaviour Work is well-known in the art and those of generally uses.Unless otherwise defined, all technologies used herein and section Technics usually has and the normally understood identical meaning of present disclosure those of ordinary skill in the art.
Term " individual " indicate animal, including but not limited to, primate (for example, people), ox, pig, sheep, goat, Horse, dog, cat, rabbit, rat or mouse.Term " individual " and " patient " use interchangeably herein, indicate that such as lactation is dynamic Object individual, such as individual human, in one embodiment, people.
" isotope enrichment " used herein indicates to have same other than the natural isotopic composition of the atom The atom of position element composition." isotope enrichment " can also indicate such compound：It contains at least one in addition to this The atom of isotopics other than the natural isotopic composition of atom.
About compound provided herein, when specific atoms position is indicated as with deuterium or when " D ", it should be understood that The abundance of deuterium at the position is substantially greater than the natural abundance of deuterium, and the natural abundance of deuterium is about 0.015%.It is indicated as having The position of deuterium usually has at least 1000 (incorporations of 15% deuterium), at least at each specified deuterium position in specific embodiments 2000 (incorporations of 30% deuterium), at least 3000 (incorporations of 45% deuterium), at least 3500 (incorporations of 52.5% deuterium), at least 4000 (60% deuteriums Incorporation), at least 4500 (incorporations of 67.5% deuterium), at least 5000 (incorporations of 75% deuterium), at least 5500 (incorporations of 82.5% deuterium), at least 6000 (incorporations of 90% deuterium), at least 6333.3 (incorporations of 95% deuterium), at least 6466.7 (incorporations of 97% deuterium), at least 6600 (99% Deuterium mix) or at least 6633.3 (incorporations of 99.5% deuterium) minimum isotope enrichment factor.
Using conventional method of analysis known to persons of ordinary skill in the art, including mass spectrography, nuclear magnetic resonance spectrometry and Crystallography, it may be determined that the isotope enrichment of compound provided herein.
Confirmed that the isotope enrichment (for example, deuterate) of drug can improve medicine for dynamic with the drug of certain classifications in the past Mechanics (" PK "), pharmacodynamics (" PD ") and toxicity spectrum.See, e.g., Lijinsky et al., Food Cosmet.Toxicol.,20:393(1982)；Lijinsky et al., J.Nat.Cancer Inst., 69:1127(1982)； Mangold et al., Mutation Res.308:33(1994)；Gordon et al., Drug Metab.Dispos., 15:589 (1987)；Zello et al., Metabolism, 43:487(1994)；Gately et al., J.Nucl.Med., 27:388(1986)； Wade D,Chem.Biol.Interact.117:191(1999)。
The isotope enrichment of drug can be used for, for example, (1) reduces or eliminates undesirable metabolin, (2) increase parent The half-life period of drug, (3) reduce the number for reaching the dosage needed for intended effect, and (4) reduce the agent reached needed for intended effect The amount of amount, (5) increase the formation (if being formed) of active metabolite, and/or (6) reduce Toxic Metabolites in specific organization In generation and/or generate for combination therapy more effective drug and/or safer drug, no matter it is described combine control Treatment is done it on purpose still unintentionally.
Atom, which is replaced with one of its isotope often, leads to the variation of the reaction rate chemically reacted.The phenomenon is claimed For kinetic isotope effect (" KIE ").For example, if c h bond (has highest in the decisive step of rate of chemical reaction The step of transition state energy) in fracture, then deuterium will cause the displacement of the hydrogen reduction of reaction rate, and the process will subtract Slowly.The phenomenon be referred to as deuterium kinetic isotope effect (" DKIE ") (see, e.g., Foster et al., Adv.Drug Res., Volume 14, the 1-36 pages (1985)；Kushner et al., Can.J.Physiol.Pharmacol., volume 77, the 79-88 pages (1999))。
The magnitude of DKIE can be expressed as given reaction that wherein c h bond is broken and wherein use the deuterium exchange phase of hydrogen With the ratio between the rate of reaction.DKIE's can range from about 1 (No Parity element effect) to very big numerical value, and such as 50 or more It is more, which means that when with deuterium exchange hydrogen the reaction can slow down 50 times or more times.High DKIE values may partly attribution In be referred to as tunnel-effect the phenomenon that, this is the result of uncertainty principle.Tunnel-effect is attributed to the small quality of hydrogen atom, and And it is related to the transition state of proton because can be formed sometimes in the presence of not required activation energy and occurs.Because deuterium has more than hydrogen Big quality, so it statistically has the much lower probability that the phenomenon occurs.
Tritium (" T ") is a kind of radioactive isotope of hydrogen, is used in research, fusion reactor, accelerator for neutron production and radiation In property drug.Tritium is in core with 2 neutrons and with the hydrogen atom of the atomic weight close to 3.It is with low-down concentration day It so exists in the environment, most frequently as T2O exists.Tritium slowly decays (half-life period=12.3 year), and emits and can not penetrate The low energy β particles of application on human skin outer layer.Interior irradiation is main hazard related with the isotope, but it must huge uptake can just make At Major health risk.Compared with deuterium, before reaching danger level, it is necessary to consume less amount of tritium.Tritium (" T ") sets hydrogen Generation stronger key even than deuterium is changed, and generates the isotope effect of bigger in number.Similarly, the isotope of other elements Displacement, including but not limited to13C or14C replaces carbon,33S、34S or36S replaces sulphur,15N replace nitrogen and17O or18O replaces oxygen, can be with Lead to similar kinetic isotope effect.
For example, DKIE is used by the generation of roughly limits reactivity substance (such as trifluoro-acetyl chloride) to reduce fluorine The hepatotoxicity wind agitation of alkane.However, this method may not be suitable for all drug categories.For example, deuterium incorporation can cause metabolism to be converted.Generation The concept for thanking to conversion claims, before chemical reaction (for example, oxidation), xenogenesis object (xenogen) can be with when being isolated by I phase enzymes Briefly combined with a variety of conformations and in conjunction with.The hypothesis is by the binding pocket with respect to huge size in many I phases enzymes The property that mixes of (binding pocket) and many metabolic responses is supported.Metabolism conversion may lead to the known of different proportion Metabolin and completely new metabolin.This new metabolic characteristics may transmit more or less toxicity.
In order to eliminate the purpose of foreign substance (such as therapeutic agent) from its circulatory system, animal body surface reaches a variety of enzymes.This The example of the enzyme of sample includes cytochrome P 450 enzymes (" CYP "), esterase, protease, reductase, dehydrogenase and monoamine oxidase, The intermediate of polarity bigger is reacted and converted it into these foreign substances or for the metabolin of renal excretion.Pharmaceutical compound The most common metabolic response of some of object is related to carbon-hydrogen (C-H) key and is oxidized to carbon-oxygen (C-O) or carbon-to-carbon (C-C) pi bond.Gained Metabolin can be stable or unstable in physiological conditions, and can have substantially not compared with parent compound Same pharmacokinetics, pharmacodynamics and acute and long term toxicity characteristic.For many drugs, such oxidation is quick 's.Therefore, these drugs are frequently necessary to the application of multiple dosage or high daily dose.
Therefore, compared with the similar compound with natural isotopic composition, in certain positions of compound provided herein It is special that the isotope enrichment at the place of setting will generate the pharmacokinetics that can influence compound provided herein, pharmacology and/or toxicology The detectable KIE of property.
Term " isotopic variations " indicates such therapeutic agent：One or more atoms of its therapeutic agent as composition Isotope of the place containing unnatural proportions.In certain embodiments, " isotopic variations " of therapeutic agent contain unnatural proportions One or more isotopes, including but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon -11 (11C), carbon -12 (12C), carbon- 13(13C), carbon-14 (14C), nitrogen -13 (13N), nitrogen -14 (14N), nitrogen -15 (15N), oxygen -14 (14O), oxygen -15 (15O), oxygen -16 (16O), oxygen -17 (17O), oxygen -18 (18O), fluoro- 17 (17F), Value linear (18F), phosphorus-31 (31P), phosphorus -32 (32P), phosphorus -33 (33P), sulphur -32 (32S), sulphur -33 (33S), sulphur -34 (34S), Sulphur-35 (35S), sulphur -36 (36S), chloro- 35 (35Cl), chloro- 36 (36Cl), chloro- 37 (37Cl), bromo- 79 (79Br), bromo- 81 (81Br), iodine 123 (123I), iodine-125 (125I), iodo- 127 (127I)、 Iodo- 129 (129I) and iodine -131 (131I).In certain embodiments, " isotopic variations " of therapeutic agent contain unnatural proportions One or more isotopes, including but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon -11 (11C), carbon -12 (12C), carbon- 13(13C), carbon-14 (14C), nitrogen -13 (13N), nitrogen -14 (14N), nitrogen -15 (15N), oxygen -14 (14O), oxygen -15 (15O), oxygen -16 (16O), oxygen -17 (17O), oxygen -18 (18O), fluoro- 17 (17F), Value linear (18F), phosphorus-31 (31P), phosphorus -32 (32P), phosphorus -33 (33P), sulphur -32 (32S), sulphur -33 (33S), sulphur -34 (34S), Sulphur-35 (35S), sulphur -36 (36S), chloro- 35 (35Cl), chloro- 36 (36Cl), chloro- 37 (37Cl), bromo- 79 (79Br), bromo- 81 (81Br), iodine 123 (123I), iodine-125 (125I), iodo- 127 (127I)、 Iodo- 129 (129I) and iodine -131 (131I)。
It should be understood that in therapeutic agent, in the case that feasible according to the judgement of technical staff, any hydrogen can be example Such as2H or any carbon can be for example13C or any nitrogen can be for example15N or any oxygen can be for example18O.In certain realities It applies in scheme, the deuterium (D) of " isotopic variations " containing unnatural proportions of therapeutic agent.
Term " treatment " be intended to include be mitigated or eliminated illness, disease or morbid state, or with illness, disease or disease shape The related one or more symptoms of state；Or the reason of mitigating or eradicating illness, disease or morbid state itself.
Term " prevention " intention includes delay and/or prevention illness, disease or morbid state and/or its simultaneous phenomenon Breaking-out；Individual is prevented to obtain illness, disease or morbid state；Or reduce the wind of the acquisition illness of individual, disease or morbid state The method of danger.
As used in this article, and unless otherwise noted, term " management " and " processing " indicate to prevent or slow down disease or The progress of illness or one or more symptom, propagation or deterioration.The advantageous effect that individual is obtained from prophylactic and/or therapeutic agent The healing of disease or illness will not often be caused.In this regard, term " management " includes the individual that treatment has suffered from specified disease To attempt to prevent or reduce the disease palindromia.
As used in this article, the symptom expression for improving particular condition by the application of certain drug composition can be with attribution Application in the composition or any mitigation related with the application of the composition, it is no matter lasting or temporary, it holds It is continuous or of short duration.
Term " illness " used herein or " obstacle " are intended to and term " disease ", " syndrome " and " morbid state " (such as in medical condition) is usually synonymous and be used interchangeably because all reflect damage normal function human or animal body or The unusual condition of one of its part is usually shown by distinguishing sign and symptom.
Term " therapeutically effective amount " intention includes the amount of such compound：When applied, it is enough to prevent treating Illness, one or more symptoms of disease or morbid state development, or mitigate to a certain extent illness being treated, One or more symptoms of disease or morbid state.Term " therapeutically effective amount " also illustrates that the amount of such compound：It is enough Cause biomolecule (for example, albumen, enzyme, RNA or DNA) that researcher, animal doctor, doctor or clinician seeking, thin Biology or the medicine response of born of the same parents, tissue, system, animal or people.
As used in this article, and unless otherwise noted, " prevention effective dose " of compound is to be enough to prevent disease or disease Disease or the amount for preventing its recurrence.The prevention effective dose of compound refers to combining individually or with one or more other reagents The amount of therapeutic agent provides in the prevention of disease and prevents benefit.Term " prevention effective dose " may include improving overall prevent Or the amount of the prevention effect of another prophylactic of enhancing.
Term " pharmaceutically acceptable carrier ", " pharmaceutically acceptable excipient ", " physiologically acceptable carrier " Or " physiologically acceptable excipient " indicates pharmaceutically acceptable substance, composition or medium, such as liquid or solid Filler, diluent, solvent or encapsulating material.In one embodiment, each component is " pharmaceutically acceptable ", is contained Justice is compatible with other ingredients of pharmaceutical preparation, and suitable for the tissue or organ of contact human and animal, without excessive Toxicity, stimulation, allergic response, immunogenicity or other problems or complication, match with rational income/Hazard ratio.Ginseng See, Remington:The Science and Practice of Pharmacy, the 22nd edition；Pharmaceutical Press:2012；Handbook of Pharmaceutical Excipients, the 7th edition；Rowe et al. is compiled；The Pharmaceutical Press:2012；Handbook of Pharmaceutical Additives, the 3rd edition；Ash and Ash It compiles；Gower Publishing Company:2007；Pharmaceutical Preformulation and Formulation, second edition；Gibson is compiled；CRC Press LLC:Boca Raton,FL,2009.
As used in specification and adjoint claim, indefinite article "one" and "an" and definite article " institute State " include plural and the signified object of odd number, unless the context clearly indicates otherwise.
Term " about " or " about " refer to particular value as one of ordinary skill in the identified acceptable error, It depends in part on how to measure or determine described value.In certain embodiments, term " about " or " about " refer to 1, 2, in 3 or 4 standard deviations.In certain embodiments, term " about " or " about " refer to given value or range 30%, 25%, in 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.05%.At certain In a little embodiments, the "about" or "approximately" about the peaks X-ray powder diffraction 2- θ refers in ± 0.2 °.
Term " active constituent " and " active material " indicate such compound：Its individually or with one or more pharmacy It is administered to upper acceptable excipient composition individual, for treating, preventing or improving illness, disease or one kind of morbid state Or a variety of symptoms." active constituent " and " active material " used herein can be the optical activities of compound described herein Isomers or isotopic variations.
Term " anti-solvent " indicates such liquid：It is added into solvent to reduce dissolving of the compound in the solvent Degree, in some cases, leads to the precipitation of the compound.
Term " drug ", " therapeutic agent " and " chemotherapeutant " represents treatment, prevention or improves illness, disease or disease One or more symptoms of diseased state and be administered to individual compound or its pharmaceutical composition.
Term " solvate " indicates the one or more molecules and solvent by solute (for example, compound provided herein) One or more molecules formed compound or aggregation, with stoichiometry or non-stoichiometric amount exist.Properly Solvent include but not limited to water, methanol, ethyl alcohol, normal propyl alcohol, isopropanol and acetic acid.In certain embodiments, the solvent It is pharmaceutically acceptable.In one embodiment, the compound or aggregation are in crystal form.In another reality It applies in scheme, the compound or aggregation are in non-crystalline forms.In the case where the solvent is water, the solvent closes Object is hydrate.The example of hydrate includes but not limited to semihydrate, monohydrate, dihydrate, trihydrate, four hydrations Object and pentahydrate.
" crystal form " of term compound can be denoted as free acid compound, as free alkali compound, As the acid-addition salts of compound, solvate (including the water of the base addition salts of compound, the compound of compound, compound Close object) or compound eutectic any crystal form." solid form " of term compound can indicate any of compound Crystal form, or the compound as free acid, the compound as free alkali, the acid-addition salts as compound, compound Base addition salts, the compound of compound, the solvate (including hydrate) of compound or compound co-precipitation it is any Amorphous form.In many cases, term " crystal form " and " solid form " can indicate it is pharmaceutically acceptable those, Including for example, pharmaceutically acceptable addition salt, pharmaceutically acceptable compound, pharmaceutically acceptable solvate, medicine Those of acceptable eutectic and pharmaceutically acceptable co-precipitation on.
" mechanical " behavior for indicating to repeat of term, repeats, or more singularly by slight variation, as a system The complicated movement of row repeats.
Term " hyperkinesia venereal disease disease " or " hyperkinesia dyskinesia " or " hyperkinesia " indicate with The conditions or diseases excessive, abnormal, involuntary movement is characterized.These illnesss include but not limited to Huntington disease, tardy Property dyskinesia, figure rett syndrome, dystonia, hemiballismus, chorea, senile chorea or twitch.
Term " neuropathic conditions " or " neurogenic disease " include but not limited to hyperkinesia venereal disease disease, biphasic or bipolar type barrier Hinder, answered after Major Depressive Disorder, anxiety, Attention deficit hyperactivity disorder, dementia, depression, insomnia, mental disease, wound Dyskinesia, dyskinesia or the oppositional defiant disorder that sharp obstacle, substance abuse, Parkinson's disease, levodopa induce.
Term " Delayed onset syndrome " includes but not limited to that tardive dyskinesia, Delayed onset dystonia, Delayed onset are quiet It sits and cannot, Delayed onset twitch, myoclonia, tremble and urgent abstinence syndrome.
Term " VMAT2 " indicates human vesicular monoamine transporter isoform 2, that is, works with by monoamine, particularly nerve Mediator (such as dopamine, norepinephrine, thrombocytin and histamine) is conveyed into from the cytosol of cell in synaptic vesicle Integrated membrane protein.
Term " illness that VMAT2 is mediated " indicates to cause other exceptions raw with abnormal VMAT2 activity or when modulated The illness that the improved VMAT2 activity of object process is characterized.The illness that VMAT2 is mediated can completely or partially pass through tune VMAT2 is saved to mediate.Specifically, the illness that VMAT2 is mediated is such illness：The wherein inhibition of VMAT2 leads to underlying conditions On certain effect, for example, the application of VMAT2 inhibitor leads to certain improvement in treated patient.
Term " VMAT2 inhibitor ", " inhibiting VMAT2 " or " inhibition of VMAT2 " indicate compound disclosed herein Change the ability of the function of VMAT2.VMAT2 inhibitor can by formed between the inhibitor and VMAT2 it is reversible or Irreversible covalent bond, or by forming the compound noncovalently combined, block or reduce the activity of VMAT2.Such suppression System can be showed only in particular cell types, or can be accidental in particular organisms event." VMAT2 inhibits term Agent ", " inhibiting VMAT2 " or " inhibition of VMAT2 " also illustrate that and form compound between VMAT2 and natural substrate by reducing Probability changes the function of VMAT2.In certain embodiments, using the method described in the following documents, it can be estimated that The adjusting of VMAT2：WO 2005/077946；WO 2008/058261；EP 1716145；Kilbourn et al., European Journal of Pharmacology1995,(278),249-252；Lee et al., J.Med.Chem., 1996, (39), 191- 196；Scherman et al., Journal of Neurochemistry 1988,50 (4), 1131-36；Kilbourn et al., Synapse 2002,43(3),188-194；Kilbourn et al., European Journal of Pharmacology 1997,331(2-3),161-68；With Erickson et al., Journal of Molecular Neuroscience 1995,6 (4),277-87。
" pharmaceutically acceptable salt " indicates any salt of compound provided herein, remains the biology of compound Characteristic and it is nontoxic or will not be not suitable in other aspects for pharmaceutical applications.Such salt can be from this field many institute's weeks The a variety of organic and inorganic counterion known is derived.Such salt includes but not limited to：(1) with organic acid or inorganic acid shape At acid-addition salts, the organic acid or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, Trifluoroacetic acid, trichloroacetic acid, propionic acid, caproic acid, cyclopentanepropanoiacid acid, oxyacetic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, amber Acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4- (2-hydroxybenzoyl)s Base) benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalandione, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethane-disulfonic acid, 2- hydroxyls Base ethanesulfonic acid, benzene sulfonic acid, 4- chlorobenzenesulfonic acids, 2- naphthalene sulfonic acids, 4- toluenesulfonic acids, camphoric acid, camphorsulfonic acid, 4- methyl bicyclics [2.2.2]-oct-2-ene -1- formic acid, glucoheptonic acid, 3- phenylpropionic acids, trimethylace tonitric, butylacetic acid, lauryl sulphur Acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic, chinic acid, muconic acid Equal acid；Or (2) acid proton (a) present in the parent compound by metal ion (such as alkali metal ion, alkaline-earth metal from Son or aluminium ion) it substitutes, or by alkali or alkaline earth metal hydroxide (such as sodium hydroxide, potassium hydroxide, hydroxide Calcium, magnesium hydroxide, aluminium hydroxide, lithium hydroxide, zinc hydroxide and barium hydroxide) or ammonia replacement, or it is (b) (all with organic base Such as aliphatic, alicyclic or aromatics organic amine, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanol amine, diethanol amine, Triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N, N '-dibenzyl-ethylenediamins, chloroprocanine, diethanol Amine, procaine, N- benzyl-1-phenylethylamines, N-METHYL-ALPHA-L-GLUCOSAMINE piperazine, three (hydroxymethyl)-aminomethanes, tetramethyl hydroxide Ammonium etc.) coordination when, forming salt.
Pharmaceutically acceptable salt further includes, merely exemplary, and is not limited to, sodium, potassium, calcium, magnesium, ammonium, tetra-allkylammonium Deng, and when compound contains basic functionality, include the salt of non-toxic organic acid or inorganic acid, such as hydrohalide, such as salt Hydrochlorate and hydrobromate, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, Propionate, caproate, cyclopentyl propionate, glycollate, glutarate, acetonate, lactate, malonate, succinic acid Salt, sorbate, ascorbate, malate, maleate, fumarate, tartrate, citrate, benzoate, 3- (4- hydroxy benzoyls) benzoate, picrate, cinnamate, mandelate, phthalate, laruate, Methane sulfonates (mesylate), esilate, 1,2- ethane-disulfonate, 2- isethionates, benzene sulfonate (benzenesulfonate, besylate), 4- closilates, 2- naphthalene sulfonates, 4- toluene fulfonates, camphor hydrochlorate, camphor tree Brain sulfonate, 4- methyl bicyclics [2.2.2]-oct-2-ene -1- formates, gluceptate, 3- phenylpropionic acids salt, trimethyl second Hydrochlorate, tebutate, lauryl sulfate, gluconate, benzoate, glutamate, Hydroxynaphthoate, bigcatkin willow Hydrochlorate, stearate, cyclohexyl-n-sulfonate, quinate, muconate etc..
Term " amino acid " indicates both naturally occurring and synthetic α, β, γ or δ amino acid, and includes but not limited in egg The amino acid found in white, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, color Propylhomoserin, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamic acid Salt, lysine, arginine and histidine.In one embodiment, the amino acid is to be in L- configurations.Alternatively, institute It can be alanyl, valyl base, leucyl-, isoleucyl-, prolyl, phenylalanyl, color ammonia to state amino acid Acyl group, methionyl, glycyl, seryl-, Threonyl, cysteinyl-, tyrosyl-, asparaginyl-, Glutaminyl, aspartoyl, glutaryl, lysyl-, arginyl-, histidyl-, β-alanyl, β-figured silk fabrics Aminoacyl, β-leucyl-, β-isoleucyl-, β-prolyl, β-phenylalanyl, β-tryptophanyl, β-methionyl Base, β-glycyl, β-seryl-, β-Threonyl, β-cysteinyl-, β-tyrosyl-, β-asparaginyl-, β- Glutaminyl, β-aspartoyl, β-glutaryl, β-lysyl-, β-arginyl- or β-histidyl- spread out Biology.
Solid form
In one embodiment, there is provided herein (S) -2- amino -3- metliyl-butyric acids (2R, 3R, 11bR) -3- isobutyls Base -9,10- dimethoxy -1,3,4,6,7,11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl esters can pharmaceutically connect The salt received or its isotopic variations.(S) -2- amino -3- metliyl-butyric acids (2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxies Base -1,3,4,6,7,11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl ester has the structure of following formula：
It can be according to U.S. Patent number 8,039,627 and 8,357,697 (each disclosure in them is by drawing Be integrally incorporated herein) prepare compound (S) -2- amino -3- metliyl-butyric acids (2R, 3R, 11bR) -3- isobutyl groups -9,10- two Methoxyl group -1,3,4,6,7,11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl ester (also referred to as valbenazine).
Valbenazine xylenesulfonates
In another embodiment, there is provided herein the 2- of the Formulas I of crystal form amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin -2- Base ester two (4- toluenesulfonates) or its isotopic variations or its solvate：
Use many methods known to those skilled in the art, including Advances in crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (for example, scanning electron microscopy (SEM)), heat analysis are (for example, differential scanning calorimetry (DSC), thermogravimetric Amount analysis (TGA) and hot microscope carrier microscopy and spectroscopic methodology (for example, infrared, Raman, solid state nmr), can characterize (for example, Formulas I) crystal form as shown in this article.By conventional method, such as laser scattering technology, it may be determined that granularity and size Distribution.Pass through standard method of analysis, such as thin-layered chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC) and mass spectrography (MS), it may be determined that the purity of crystal form provided herein.
Valbenazine xylene monosulfonic acid salt forms I
In another embodiment, there is provided herein the 2- of crystal form amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester Two (4- toluenesulfonates) (Formulas I) or its isotopic variations or its solvate；The wherein described crystal form is form I.
In different implementation scenarios, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- bis- Two (4- toluenesulfonates) (formula of methoxyl group -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester I crystal form I) has X-ray diffraction pattern.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester The X-ray diffraction pattern of the form I of two (4- toluenesulfonates) (Formulas I) is included in about 6.3,17.9 and 19.7 ° of 2- θ XRP diffraction maximums at angle.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups - Two (4- toluenesulfonic acids of 9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Salt) XRP that is included at about 6.3,17.9 or 19.7 ° of the angles 2- θ of X-ray powder diffraction figure sample of form I of (Formulas I) spreads out Penetrate peak.In another embodiment, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- diformazans Oxygroup -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) Crystal form I be included in the XRP diffraction maximums at about 6.3 ° and 19.7 ° of the angles 2- θ.In another embodiment, 2- ammonia Base -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrroles The crystal form I of pyridine simultaneously [2,1-a] isoquinolin-2-yl ester two (4- toluenesulfonates) (Formulas I) is included in about 6.3 ° of 2- θ XRP diffraction maximums at angle.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups - Two (4- toluenesulfonic acids of 9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Salt) (Formulas I) crystal form I have X-ray diffraction pattern substantially as shown in FIG. 1.
In certain embodiments, crystal form I has one or more angles 2- θ at about 6.3 ° and about 19.7 ° The characteristic XRP diffraction maximums at place.In certain embodiments, crystal form I have it is one or more about 6.3 °, about Characteristic XRP diffraction maximums at 17.9 ° and about 19.7 ° of the angles 2- θ.In certain embodiments, there are one crystal form I tools Or multiple characteristic XRP diffraction maximums at about 6.3 °, about 17.9 °, about 19.7 ° and about 22.7 ° of the angles 2- θ. In certain embodiments, crystal form I have it is one or more about 6.3 °, about 15.6 °, about 17.9 °, about Characteristic XRP diffraction maximums at 19.7 ° and about 22.7 ° of the angles 2- θ.In certain embodiments, there are one crystal form I tools Or it is multiple at about 6.3 °, about 15.6 °, about 16.6 °, about 17.9 °, about 19.7 ° and about 22.7 ° of the angles 2- θ Characteristic XRP diffraction maximums.
In different implementation scenarios, crystal form I has heat absorption differential scanning calorimetry (DSC) thermogram.Certain In embodiment, it includes with about 240 DEG C of start temperature and at about 243 DEG C that crystal form I, which has DSC thermograms, the figure, The endothermic event at the peak at place.In another embodiment, crystal form I is with DSC warm substantially as shown in Figure 2 point Analysis figure.In another embodiment, crystal form I has thermogravimetry (TGA) figure, and it includes work as from about 25 DEG C to be heated to Mass loss at about 140 DEG C less than about 0.4%.In another embodiment, crystal form I has substantially such as in Fig. 2 Shown in TGA figure.
In different implementation scenarios, crystal form I has gravimetric analysis vapour system (GVS) figure.In certain embodiment party In case, when the relative humidity for undergoing from about 0% to about 95% relative humidity increases, crystal form I shows about 1% quality Increase.In certain embodiments, when relative humidity (RH) is dropped back to about 0%RH, when absorption, increased quality was lost.Another In one embodiment, crystal form I shows gravimetric analysis vapour system figure substantially as shown in Figure 3.Another In a embodiment, when being exposed to about 25 DEG C and about 60% relative humidity, crystal form I is stable.In another embodiment party In case, when being exposed to about 25 DEG C and about 60% relative humidity about 24 months, crystal form I is stable.Also in another implementation In scheme, when being exposed to about 25 DEG C and about 60% relative humidity about 3 months, crystal form I is stable.In another embodiment party In case, when being exposed to about 25 DEG C and about 92% relative humidity, crystal form I is stable.In another embodiment, when sudden and violent About 40 DEG C and about 75% relative humidity are exposed to, crystal form I is stable.In another embodiment, when being exposed to about 40 DEG C and about 75% relative humidity about 6 months, crystal form I is stable.In another embodiment, when being exposed to about 40 DEG C About 75% relative humidity about 3 months, crystal form I is stable.
In certain embodiments, not less than about 95 weight %, no can be contained by being in the crystal form of the Formulas I of form I Less than about 97 weight %, not less than about 98 weight %, not less than about 99 weight % or the not less than about Formulas I of 99.5 weight % Salt.The crystal form can also contain not less than about 90 weight %, not less than about 95 weight %, not less than about 98 weight %, The not less than about 99 weight % or crystal form I not less than 99.5 weight %.
In certain embodiments, crystal form I have about 17.58, about 18.58, about 19.58, about 26.75, about 26.87, about 26.96, about 27.06, about 27.75, about 27.87, about 27.97, about 28.06, about 28.75, about 28.87, about 28.97, about 29.06, about 27.45, about 28.45, about 29.45, about 30.61, about 31.61, about 32.61, about 32.17, about 32.98, the water solubility of about 33.17, about 33.98, about 34.17, about 34.35, about 34.98, about 35.35, about 36.35mg/mL. In certain embodiments, the water solubility that it is about 31.61 and about 33.17 in about pH 1.2 that crystal form I, which has,；Big It is about 28.45 and about 27.97 water solubility when about pH 3；The water dissolution for being about 28.06 and about 27.77 in about pH 4 Degree；The water solubility for being about 18.58 and about 27.87 in about pH 5；It is about 33.98 and about 35.35 in about pH 6.8 Water solubility.
In certain embodiments, by weight, crystal form I, which can contain, is not greater than about 0.1%, is not greater than about 0.11%, no more than about 0.12%, no more than about 0.13%, no more than about 0.14%, no more than about 0.15%, be not greater than about 0.16%, no more than about 0.17%, no more than about 0.18%, no more than about 0.19%, no more than about 0.2%, be not greater than about 0.21%, no more than about 0.22%, no more than about 0.23%, no more than about 0.24%, no more than about 0.25%, be not greater than about 0.26%, no more than about 0.27%, no more than about 0.28%, no more than about 0.29%, no more than about 0.3%, be not greater than about 0.31%, no more than about 0.32%, no more than about 0.33%, no more than about 0.34%, no more than about 0.35%, be not greater than about 0.36%, no more than about 0.37%, no more than about 0.38%, no more than about 0.39%, no more than about 0.4%, be not greater than about 0.5%, be not greater than about 0.6%, no more than about 0.7%, no more than about 0.8%, no more than about 0.9%, no more than about 1%, no Greater than about 2%, no more than about the 3%, water no more than about 4% or no more than about 5%.
It in certain embodiments, can be by grading analysis come forms of characterization I.In certain embodiments, form I Sample includes the particle with rhombohedral crystal morphology.In another embodiment, the sample of form I include about 100, about 90, The particle of about 80, about 70, about 60, about 50, about 40, about 30, about 20, about 10, about 5 μM of length.In certain embodiments, form The sample of I includes the particle of about 70, about 60, about 40, about 20, about 10 μM of length.In other embodiments, the sample of form I Include the particle of about 69.39, about 56.22, about 34.72, about 17.84, about 10.29 μM of length.
Valbenazine xylene monosulfonic acid salt forms II
In another embodiment, be crystal form 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- it is different Two (4- methyl of butyl -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Benzene sulfonate) (Formulas I) or its isotopic variations or its solvate；The wherein described crystal form is form II.
In different implementation scenarios, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- bis- Two (4- toluenesulfonates) (formula of methoxyl group -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester I crystalline Formula II) has X-ray diffraction pattern.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin -2- The X-ray diffraction pattern of the form II of base ester two (4- toluenesulfonates) (Formulas I) is included in about 5.7,15.3 and 22.5 ° The angles 2- θ at XRP diffraction maximums.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- is different Two (4- methyl of butyl -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Benzene sulfonate) the X-ray powder diffraction figure sample of form II of (Formulas I) is included at about 5.7,15.3 or 22.5 ° of the angles 2- θ XRP diffraction maximums.In other embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- Dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) The X-ray powder diffraction figure sample of the form II of (Formulas I) is included in the XRP diffraction maximums at about 5.7 and 15.3 ° of the angles 2- θ. In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxys -2,3, The form II's of 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) X-ray powder diffraction figure sample is included in the XRP diffraction maximums at about 5.7 ° of the angles 2- θ.In certain embodiments, 2- amino- 3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyridines And the crystalline Formula II of [2,1-a] isoquinolin-2-yl ester two (4- toluenesulfonates) (Formulas I) has substantially as in Figure 5 Shown in X-ray diffraction pattern.
In certain embodiments, crystalline Formula II has one or more at about 5.7 and 15.3 ° of the angles 2- θ Characteristic XRP diffraction maximums.In certain embodiments, crystalline Formula II has one or more at about 5.7 °, about 15.3 ° Characteristic XRP diffraction maximums at about 22.5 ° of the angles 2- θ.In certain embodiments, crystalline Formula II has one or more A characteristic XRP diffraction maximums at about 5.7 °, about 14.2 °, about 15.3 ° and about 22.5 ° of the angles 2- θ.Other In embodiment, crystalline Formula II have one or more at about 5.7 °, about 14.2 °, about 15.3 °, about 15.9 ° and Characteristic XRP diffraction maximums at about 22.5 ° of the angles 2- θ.In other embodiments, crystalline Formula II has one or more Feature at about 5.7 °, about 14.2 °, about 15.3 °, about 15.9 °, about 18.6 ° and about 22.5 ° of the angles 2- θ Property XRP diffraction maximums.
In different implementation scenarios, crystalline Formula II has heat absorption differential scanning calorimetry (DSC) thermogram.Certain In embodiment, crystalline Formula II have DSC thermograms, it includes with about 143 DEG C start temperature and at about 155 DEG C Peak an endothermic event and another endothermic event with about 232 DEG C of start temperature and the peak at about 235 DEG C.
In another embodiment, crystalline Formula II has DSC thermograms substantially as shown in FIG. 6. In another embodiment, crystalline Formula II has thermogravimetry (TGA) figure, and it includes work as from about 25 DEG C to be heated to about 140 DEG C when about 2.2% mass loss.In another embodiment, crystalline Formula II has substantially as shown in FIG. 6 TGA schemes.
In different implementation scenarios, crystalline Formula II has gravimetric analysis vapour system (GVS) figure.In certain embodiment party In case, when the relative humidity for undergoing from about 0% to about 95% relative humidity increases, crystalline Formula II shows about 0.5% Quality increases.In certain embodiments, when relative humidity (RH) is dropped back to about 0%RH, when absorption, increased quality was lost. In another embodiment, crystalline Formula II shows gravimetric analysis vapour system figure substantially as shown in FIG. 7. In certain embodiments, form II is substantially nonhygroscopic.In certain embodiments, after adsorption/desorption analysis, shape The XRPD patterns of Formula II substance there is no variation.In certain embodiments, form II is stable for humidity 's.In another embodiment, crystalline Formula II has the water solubility of the about 18.5mg/mL in pH 5.1.
In certain embodiments, grading analysis forms of characterization II can be passed through.In certain embodiments, form II Sample includes the particle with birefringent plate lath-like morphologies.In another embodiment, the sample of form II include about 100, The particle of about 90, about 80, about 70, about 60, about 50, about 40, about 30, about 20, about 10, about 5 μM of length.In certain embodiments In, the sample of form II includes the particle of about 100, about 70, about 60, about 40, about 20, about 10 μM of length.In another embodiment party In case, the sample of form II includes the particle of about 100 μM of length.
In certain embodiments, not less than about 95 weight %, no can be contained by being in the crystal form of the Formulas I of form II Less than about 97 weight %, not less than about 98 weight %, not less than about 99 weight % or the not less than about Formulas I of 99.5 weight % Salt.The crystal form can also contain not less than about 90 weight %, not less than about 95 weight %, not less than about 98 weight %, Not less than about 99 weight % or the crystalline Formula II not less than 99.5 weight %.
Valbenazine xylene monosulfonic acid salt forms III
In another embodiment, be crystal form 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- it is different Two (4- methyl of butyl -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Benzene sulfonate) (Formulas I) or its isotopic variations or its solvate；The wherein described crystal form is form III.
In different implementation scenarios, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- bis- Two (4- toluenesulfonates) (formula of methoxyl group -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester I crystalline formula III) has X-ray diffraction pattern.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin -2- The X-ray diffraction pattern of the form III of base ester two (4- toluenesulfonates) (Formulas I) is included in about 6.3,18.3,18.9, XRP diffraction maximums at 19.8 and 20.4 ° of the angles 2- θ.In another embodiment, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin -2- The X-ray diffraction pattern of the form III of base ester two (4- toluenesulfonates) (Formulas I) is included in about 6.3,18.3,18.9, XRP diffraction maximums at 19.8 or 20.4 ° of the angles 2- θ.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester The X-ray diffraction pattern of the form III of two (4- toluenesulfonates) (Formulas I) is included in about 6.3,18.3 and 19.8 ° of 2- XRP diffraction maximums at the angles θ.In other embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups - Two (4- toluenesulfonic acids of 9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Salt) X-ray diffraction pattern of form III of (Formulas I) is included in the XRP diffraction maximums at about 6.3 ° of the angles 2- θ.In certain realities It applies in scheme, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxys -2,3,4,6,7, The crystalline formula III of 11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) has There is X-ray diffraction pattern substantially as shown in FIG. 8.
In certain embodiments, crystalline formula III has one or more in about 6.3 ° and about 19.8 ° of 2- θ Characteristic XRP diffraction maximums at angle.In certain embodiments, crystalline formula III have it is one or more about 6.3 °, it is big Characteristic XRP diffraction maximums at about 18.3 ° and about 19.8 ° of the angles 2- θ.In other embodiments, crystalline formula III has Characteristic XRP diffraction of the one or more at about 6.3 °, about 18.3 °, about 19.8 ° and about 20.4 ° of the angles 2- θ Peak.In certain embodiments, crystalline formula III have it is one or more about 6.3 °, about 18.3 °, about 18.9 °, Characteristic XRP diffraction maximums at about 19.8 ° and about 20.4 ° of the angles 2- θ.In other embodiments, crystalline formula III has There are one or multiple 2- at about 6.3 °, about 15.3 °, about 18.3 °, about 18.9 °, about 19.8 ° and about 20.4 ° Characteristic XRP diffraction maximums at the angles θ.In certain embodiments, crystalline formula III have it is one or more about 6.3 °, Characteristic at about 15.3 °, about 18.3 °, about 18.9 °, about 19.8 °, about 20.4 ° and about 24.1 ° of the angles 2- θ XRP diffraction maximums.
In different implementation scenarios, crystalline formula III has heat absorption differential scanning calorimetry (DSC) thermogram.At certain In a little embodiments, it includes with about 93 DEG C, 158 DEG C and about 230 DEG C of peak that crystalline formula III, which has DSC thermograms, the figure, The endothermic event of temperature.
In another embodiment, crystalline formula III has DSC thermograms substantially as shown in FIG. 9. In another embodiment, crystalline formula III has thermogravimetry (TGA) figure, and it includes work as from about 25 DEG C to be heated to about 140 DEG C when about 2.7% and about 8.86% two kinds of mass losses.In another embodiment, crystalline formula III has substantially TGA figures as shown in FIG. 9.
In certain embodiments, grading analysis forms of characterization III can be passed through.In certain embodiments, form III Sample include with birefringent plate lath-like morphologies particle.In another embodiment, the sample of form III includes about 100, the particle of about 90, about 80, about 70, about 60, about 50, about 40, about 30, about 20, about 10, about 5 μM of length.In certain embodiment party In case, the sample of form III includes the particle of about 100, about 70, about 60, about 40, about 20, about 10 μM of length.
In certain embodiments, be in form III Formulas I crystal form can contain not less than about 95 weight %, Not less than about 97 weight %, not less than about 98 weight %, not less than about 99 weight % or the not less than about Formulas I of 99.5 weight % Salt.The crystal form can also contain not less than about 90 weight %, not less than about 95 weight %, not less than about 98 weight %, Not less than about 99 weight % or the crystalline formula III not less than 99.5 weight %.
Valbenazine xylene monosulfonic acid salt forms IV
In another embodiment, be crystal form 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- it is different Two (4- methyl of butyl -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Benzene sulfonate) (Formulas I) or its isotopic variations or its solvate；The wherein described crystal form is form IV.
In different implementation scenarios, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- bis- Two (4- toluenesulfonates) (formula of methoxyl group -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester I crystalline formula IV) has X-ray diffraction pattern.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin -2- The X-ray diffraction pattern of the form IV of base ester two (4- toluenesulfonates) (Formulas I) is included in about 6.2,10.4,17.9, 19.2, the XRP diffraction maximums at 19.9 and 20.2 ° of the angles 2- θ.In certain embodiments, 2- amino -3 Methylbutanoic acid (S) - (2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinoline The X-ray powder diffraction figure sample of the form IV of quinoline -2- base esters two (4- toluenesulfonates) (Formulas I) is included in about 6.2, 10.4, the XRP diffraction maximums at 17.9,19.2,19.9 or 20.2 ° of the angles 2- θ.In other embodiments, 2- amino -3- methyl Butyric acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1- A] the X-ray powder diffraction figure sample of form IV of isoquinolin-2-yl ester two (4- toluenesulfonates) (Formulas I) is included in about XRP diffraction maximums at 6.2 ° and about 20.2 ° of the angles 2- θ.In certain embodiments, 2- amino -3 Methylbutanoic acid (S) - (2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinoline The X-ray powder diffraction figure sample of the form IV of quinoline -2- base esters two (4- toluenesulfonates) (Formulas I) is included in about 6.2 ° XRP diffraction maximums at the angles 2- θ.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyls Two (4- methylbenzenes of base -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Sulfonate) (Formulas I) crystalline formula IV have X-ray diffraction pattern substantially as shown in Figure 10.
In certain embodiments, crystalline formula IV has one or more angles 2- θ at about 6.2 ° and about 20.2 ° The characteristic XRP diffraction maximums at place.In certain embodiments, crystalline formula IV have it is one or more about 6.2 °, about Characteristic XRP diffraction maximums at 10.4 ° and about 20.2 ° of the angles 2- θ.In other embodiments, crystalline formula IV has one A or multiple characteristic XRP diffraction maximums at about 6.2 °, about 10.4 °, about 17.9 ° and about 20.2 ° of the angles 2- θ. In certain embodiments, crystalline formula IV have it is one or more about 6.2 °, about 10.4 °, about 17.9 °, about Characteristic XRP diffraction maximums at 19.2 ° and about 20.2 ° of the angles 2- θ.In other embodiments, crystalline formula IV has one A or multiple angles 2- θ at about 6.2 °, about 10.4 °, about 17.9 °, about 19.2 °, about 19.9 ° and about 20.2 ° The characteristic XRP diffraction maximums at place.
In different implementation scenarios, crystalline formula IV has heat absorption differential scanning calorimetry (DSC) thermogram.Certain In embodiment, it includes with about 128 DEG C, 159 DEG C and about 237 DEG C of peak temperature that crystalline formula IV, which has DSC thermograms, the figure, The endothermic event of degree.
In another embodiment, crystalline formula IV has DSC thermograms substantially as shown in Figure 11. In another embodiment, crystalline formula IV has thermogravimetry (TGA) figure, and it includes work as from about 25 DEG C to be heated to about 140 DEG C when about 3.3% mass loss.In another embodiment, crystalline formula IV has substantially as shown in Figure 11 TGA schemes.
In different implementation scenarios, crystalline formula IV has gravimetric analysis vapour system (GVS) figure.In certain embodiment party In case, when the relative humidity for undergoing from about 0% to about 95% relative humidity increases, crystalline formula IV shows about 3.4% Quality increases.In certain embodiments, when the relative humidity for undergoing from about 40% to about 95% relative humidity increases, crystallization The quality that form IV shows about 1.6% increases.In certain embodiments, when relative humidity (RH) is dropped back to about 0%RH, Increased quality is lost when absorption.In certain embodiments, when relative humidity is fallen to approximately between 40 and 0%RH, 1.8% Quality is lost.In another embodiment, crystalline formula IV shows gravimetric analysis steaming substantially as shown in Figure 12 Vapour system diagram.In certain embodiments, after adsorption/desorption analysis, the XRPD patterns of form IV substances there is no Variation.In certain embodiments, form IV is stable for humidity.In certain embodiments, form IV is Substantially stablize.In another embodiment, when being exposed to solvent system at 30 DEG C, (it includes such as acetonitrile/waters Mixture) about 2 days, form IV is converted to form I.In another embodiment, when the sample of form IV is existed at room temperature Slurrying body, form IV are converted to form I again in acetonitrile.In another embodiment, when being heated to about 230 DEG C, form IV It is converted to form I.
In certain embodiments, grading analysis forms of characterization IV can be passed through.In another embodiment, form IV Sample include the particle of about 100, about 90, about 80, about 70, about 60, about 50, about 40, about 30, about 20, about 10, about 5 μM of length. In certain embodiments, the sample of form IV includes the particle of about 100, about 70, about 60, about 40, about 20, about 10 μM of length.
In certain embodiments, not less than about 95 weight %, no can be contained by being in the crystal form of the Formulas I of form IV Less than about 97 weight %, not less than about 98 weight %, not less than about 99 weight % or the not less than about Formulas I of 99.5 weight % Salt.The crystal form can also contain not less than about 90 weight %, not less than about 95 weight %, not less than about 98 weight %, Not less than about 99 weight % or the crystalline formula IV not less than 99.5 weight %.
Valbenazine xylene monosulfonic acid salt forms V
In another embodiment, be crystal form 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- it is different Two (4- methyl of butyl -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Benzene sulfonate) (Formulas I) or its isotopic variations or its solvate；The wherein described crystal form is form V.
In different implementation scenarios, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- bis- Two (4- toluenesulfonates) (formula of methoxyl group -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester I crystal form V) has X-ray diffraction pattern.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester The X-ray diffraction pattern of the form V of two (4- toluenesulfonates) (Formulas I) is included in about 6.7,7.9,10.7,12.8, XRP diffraction maximums at 17.1 and 23.7 ° of the angles 2- θ.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester The X-ray powder diffraction figure sample of the form V of two (4- toluenesulfonates) (Formulas I) is included in about 6.7,7.9,10.7, 12.8, the XRP diffraction maximums at 17.1 or 23.7 ° of the angles 2- θ.In certain embodiments, 2- amino -3 Methylbutanoic acid (S) - (2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinoline The X-ray powder diffraction figure sample of the form V of quinoline -2- base esters two (4- toluenesulfonates) (Formulas I) be included in about 6.7 ° and XRP diffraction maximums at 7.9 ° of the angles 2- θ.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) - Two (4- of 3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Toluenesulfonate) the X-ray powder diffraction figure sample of form V of (Formulas I) is included in the XRP diffraction at about 6.7 ° of the angles 2- θ Peak.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxy - The crystallization of 2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) Form V has X-ray diffraction pattern substantially as shown in Figure 13.
In certain embodiments, crystal form V has one or more at about 6.7 ° and about 7.9 ° of the angles 2- θ Characteristic XRP diffraction maximums.In certain embodiments, crystal form V has one or more at about 6.7 °, about 7.9 ° Characteristic XRP diffraction maximums at about 23.7 ° of the angles 2- θ.In certain embodiments, there are one crystal form V tools or more A characteristic XRP diffraction maximums at about 6.7 °, about 7.9 °, about 17.1 ° and about 23.7 ° of the angles 2- θ.In other realities It applies in scheme, crystal form V has one or more at about 6.7 °, about 7.9 °, about 15.8 °, about 17.1 ° and about Characteristic XRP diffraction maximums at 23.7 ° of the angles 2- θ.In certain embodiments, crystal form V has one or more big Characteristic XRP at about 6.7 °, about 7.9 °, about 15.8 °, about 17.1 °, about 21.5 ° and about 23.7 ° of the angles 2- θ Diffraction maximum.In certain embodiments, crystal form V have it is one or more about 6.7 °, about 7.9 °, about 15.8 °, Characteristic XRP diffraction maximums at about 16.0 °, about 17.1 °, about 21.5 ° and about 23.7 ° of the angles 2- θ.In other implementations In scheme, crystal form V have it is one or more about 6.7 °, about 7.9 °, about 10.7 °, about 15.8 °, about Characteristic XRP diffraction maximums at 16.0 °, about 17.1 °, about 21.5 ° and about 23.7 ° of the angles 2- θ.In certain embodiments In, crystal form V have it is one or more about 6.7 °, about 7.9 °, about 10.7 °, about 12.8 °, about 15.8 °, Characteristic XRP diffraction maximums at about 16.0 °, about 17.1 °, about 21.5 ° and about 23.7 ° of the angles 2- θ.
In different implementation scenarios, crystal form V has heat absorption differential scanning calorimetry (DSC) thermogram.Certain In embodiment, it includes the suction with about 113 DEG C and about 181 DEG C of peak temperature that crystal form V, which has DSC thermograms, the figure, Incident heat.
In another embodiment, crystal form V has DSC thermograms substantially as shown in Figure 14. In another embodiment, crystal form V has thermogravimetry (TGA) figure, and it includes work as from about 25 DEG C to be heated to about 140 DEG C When about 4.1% mass loss.In another embodiment, crystal form V has TGA substantially as shown in Figure 14 Figure.
In different implementation scenarios, crystal form V has gravimetric analysis vapour system (GVS) figure.In certain embodiment party In case, when the relative humidity for undergoing from about 10% to about 95% relative humidity increases, crystal form V shows about 1% matter Amount increases.In certain embodiments, when relative humidity (RH) is dropped back to about 0%RH, when absorption, increased quality was lost. In certain embodiments, when relative humidity is fallen to approximately between 20 and 0%RH, 1.2% mass is lost.In another embodiment party In case, crystal form V shows gravimetric analysis vapour system figure substantially as shown in Figure 15.In certain embodiments In, after adsorption/desorption analysis, the XRPD patterns of form V substances there is no variation.In certain embodiments, shape Formula V is substantially stable.In another embodiment, when being heated to about between 110 DEG C and about 140 DEG C, form V is converted to Form VI.
In certain embodiments, grading analysis forms of characterization V can be passed through.In another embodiment, form V Sample includes the particle of about 100, about 90, about 80, about 70, about 60, about 50, about 40, about 30, about 20, about 10, about 5 μM of length. In certain embodiments, the sample of form V includes the particle of about 100, about 70, about 60, about 40, about 20, about 10 μM of length.
In certain embodiments, not less than about 95 weight %, no can be contained by being in the crystal form of the Formulas I of form V Less than about 97 weight %, not less than about 98 weight %, not less than about 99 weight % or the not less than about Formulas I of 99.5 weight % Salt.The crystal form can also contain not less than about 90 weight %, not less than about 95 weight %, not less than about 98 weight %, The not less than about 99 weight % or crystal form V not less than 99.5 weight %.
Valbenazine xylene monosulfonic acid salt forms VI
In another embodiment, be crystal form 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- it is different Two (4- methyl of butyl -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Benzene sulfonate) (Formulas I) or its isotopic variations or its solvate；The wherein described crystal form is form VI.
In different implementation scenarios, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- bis- Two (4- toluenesulfonates) (formula of methoxyl group -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester I crystalline Formula IV) has X-ray diffraction pattern.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin -2- The X-ray diffraction pattern of the form VI of base ester two (4- toluenesulfonates) (Formulas I) is included in about 6.8,8.0,16.3 and XRP diffraction maximums at 17.5 ° of the angles 2- θ.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) - Two (4- of 3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Toluenesulfonate) the X-ray powder diffraction figure sample of form VI of (Formulas I) is included in about 6.8,8.0,16.3 or 17.5 ° XRP diffraction maximums at the angles 2- θ.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyls Two (4- methylbenzenes of base -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Sulfonate) XRP that is included at about 6.8 ° and 8.0 ° of the angles 2- θ of X-ray powder diffraction figure sample of form VI of (Formulas I) spreads out Penetrate peak.In other embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxies Base -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) The X-ray powder diffraction figure sample of form VI is included in the XRP diffraction maximums at about 6.8 ° of the angles 2- θ.In certain embodiments In, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxys -2,3,4,6,7,11b- six The crystalline Formula IV of hydrogen -1H- pyrido [2,1-a] isoquinolin-2-yls ester two (4- toluenesulfonates) (Formulas I) has substantially X-ray diffraction pattern as shown in Figure 16.
In certain embodiments, crystalline Formula IV has one or more angles 2- θ at about 6.8 ° and about 8.0 ° The characteristic XRP diffraction maximums at place.In certain embodiments, crystalline Formula IV have it is one or more about 6.8 °, about Characteristic XRP diffraction maximums at 5.4 ° and about 8.0 ° of the angles 2- θ.In other embodiments, crystalline Formula IV has one Or multiple characteristic XRP diffraction maximums at about 6.8 °, about 5.4 ° and about 8.0 ° and about 17.5 ° of the angles 2- θ.At it In its embodiment, crystalline Formula IV has one or more at about 6.8 °, about 5.4 ° and about 8.0 °, about 16.3 ° Characteristic XRP diffraction maximums at about 17.5 ° of the angles 2- θ.In other embodiments, crystalline Formula IV has one or more A feature at about 6.8 °, about 5.4 °, about 8.0 °, about 16.3 °, about 17.5 ° and about 18.7 ° of the angles 2- θ Property XRP diffraction maximums.
In different implementation scenarios, crystalline Formula IV has heat absorption differential scanning calorimetry (DSC) thermogram.Certain In embodiment, it includes the suction with about 175 DEG C and about 238 DEG C of peak temperature that crystalline Formula IV, which has DSC thermograms, the figure, Incident heat.
In another embodiment, crystalline Formula IV has DSC thermograms substantially as shown in Figure 17. In another embodiment, crystalline Formula IV has thermogravimetry (TGA) figure, and it includes work as from about 25 DEG C to be heated to about 140 DEG C when about 1% mass loss.In another embodiment, crystal form V has TGA substantially as shown in Figure 17 Figure.
In different implementation scenarios, crystalline Formula IV has gravimetric analysis vapour system (GVS) figure.In certain embodiment party In case, when the relative humidity for undergoing from about 0% to about 90% relative humidity increases, crystalline Formula IV shows about 3.1% Quality increases.In certain embodiments, when the relative humidity for undergoing from about 40% to about 80% relative humidity increases, crystallization The quality that form VI shows about 0.5% increases.In certain embodiments, when from about 80% to about 90% relative humidity of experience Relative humidity increase when, crystalline Formula IV show about 3.1% quality increase.In certain embodiments, when relatively wet Degree (RH) is when dropping back to about 0%RH, and when absorption, increased quality was not lost.In certain embodiments, when under relative humidity When being down between about 90% and 15%RH, 1.2% mass is lost.In certain embodiments, when relative humidity is fallen to approximately When between 15% and 0%RH, 2.0% mass is lost.In another embodiment, crystalline Formula IV shows substantially such as to exist Gravimetric analysis vapour system figure shown in Figure 18.In certain embodiments, after adsorption/desorption analysis, form VI objects The XRPD patterns of matter substantially change.In another embodiment, when be exposed to gravimetric analysis vapor absorption analysis, form VI It is converted to form V.
In certain embodiments, grading analysis forms of characterization VI can be passed through.In another embodiment, form VI Sample include the particle of about 100, about 90, about 80, about 70, about 60, about 50, about 40, about 30, about 20, about 10, about 5 μM of length. In certain embodiments, the sample of form VI includes the particle of about 100, about 70, about 60, about 40, about 20, about 10 μM of length.
In certain embodiments, not less than about 95 weight %, no can be contained by being in the crystal form of the Formulas I of form VI Less than about 97 weight %, not less than about 98 weight %, not less than about 99 weight % or the not less than about Formulas I of 99.5 weight % Salt.The crystal form can also contain not less than about 90 weight %, not less than about 95 weight %, not less than about 98 weight %, Not less than about 99 weight % or the crystalline Formula IV not less than 99.5 weight %.
In another embodiment, the 2- amino of crystal form -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyls Two (4- methylbenzenes of base -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester Sulfonate) (Formulas I) or its isotopic variations or its solvate be amorphous.The amorphous form, which has, substantially such as to exist X-ray powder diffraction figure sample shown in Figure 19 lacks form I and/or form II to the characteristic of the particle of form VI XRP diffraction maximums.In one embodiment, the amorphous form of the Formulas I can contain not less than about 95 weight %, be not less than The acid of about 97 weight %, not less than about 98 weight %, not less than about 99 weight % or the not less than about Formulas I of 99.5 weight %.Institute Not less than about 90 weight %, not less than about 95 weight %, not less than about 98 weight %, not small can also be contained by stating amorphous form In about 99 weight % or the amorphous form of Formulas I not less than 99.5 weight %.
Valbenazine dihydrochlorides
There is provided herein the 2- of the Formula II of crystal form amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups - 9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochlorides or it is same The plain variant in position or its solvate：
Valbenazine dihydrochloride forms I
In another embodiment, be crystal form 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- it is different Butyl -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochloride (Formula II) or its isotopic variations or its solvate；The wherein described crystal form is form I.
In different implementation scenarios, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- bis- The crystalline of methoxyl group -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochlorides (Formula II) Formulas I has X-ray diffraction pattern.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- is different Butyl -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochloride The X-ray diffraction pattern of the form I of (Formula II) is included in the XRP diffraction maximums at about 7.2,9.2 and 18.0 ° of the angles 2- θ. In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxys -2,3, The X-ray powder of the form I of 4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochlorides (Formula II) Diffraction pattern is included in the XRP diffraction maximums at about 7.2,9.2 or 18.0 ° of the angles 2- θ.In certain embodiments, 2- amino- 3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyridines And the X-ray powder diffraction figure sample of the form I of [2,1-a] isoquinolin-2-yl ester dihydrochloride (Formula II) is included in about 7.2 With the XRP diffraction maximums at 9.2 ° of the angles 2- θ.In other embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester The X-ray powder diffraction figure sample of the form I of dihydrochloride (Formula II) is included in the XRP diffraction maximums at about 7.2 ° of the angles 2- θ. In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxy -2, The crystal form I of 3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochlorides (Formula II) has base X-ray diffraction pattern as shown in Figure 20 in sheet.
In certain embodiments, the crystal form I of Formula II has one or more at about 7.2 ° and about 9.2 ° Characteristic XRP diffraction maximums at the angles 2- θ.In certain embodiments, the crystal form I of Formula II has one or more about Characteristic XRP diffraction maximums at 7.2 °, about 9.2 ° and about 18.0 ° of the angles 2- θ.In certain embodiments, the knot of Formula II Crystalline form I has one or more features at about 7.2 °, about 9.2 °, about 18.0 ° and about 20.8 ° of the angles 2- θ Property XRP diffraction maximums.In other embodiments, the crystal form I of Formula II have it is one or more about 7.2 °, about Characteristic XRP diffraction maximums at 9.2 °, about 18.0 °, about 20.8 ° and about 25.9 ° of the angles 2- θ.In certain embodiments In, the crystal form I of Formula II have it is one or more about 7.2 °, about 9.2 °, about 18.0 °, about 20.8 °, about Characteristic XRP diffraction maximums at 22.5 ° and about 25.9 ° of the angles 2- θ.In certain embodiments, the crystal form I tools of Formula II There are one or it is multiple at about 7.2 °, about 9.2 °, about 12.7 °, about 18.0 °, about 20.8 °, about 22.5 ° and about Characteristic XRP diffraction maximums at 25.9 ° of the angles 2- θ.In other embodiments, there are one the crystal form I tools of Formula II or more It is a at about 7.2 °, about 9.2 °, about 12.7 °, about 18.0 °, about 20.8 °, about 22.5 °, about 24.0 ° and about Characteristic XRP diffraction maximums at 25.9 ° of the angles 2- θ.
In different implementation scenarios, the crystal form I of Formula II has heat absorption differential scanning calorimetry (DSC) thermogram. In certain embodiments, crystal form I has DSC thermograms, and the figure is with about 240 DEG C of start temperature and about 250 The endothermic event at the peak at DEG C.
In another embodiment, the crystal form I of Formula II has DSC heat analysis substantially as shown in Figure 21 Figure.In another embodiment, the crystal form I of Formula II has thermogravimetry substantially as shown in Figure 21 (TGA) figure.
In different implementation scenarios, the crystal form I of Formula II has gravimetric analysis vapour system (GVS) figure.Certain In embodiment, when the relative humidity for undergoing from about 0% to about 90% relative humidity increases, crystal form I is shown about 14% quality increases.In another embodiment, the crystal form I of Formula II is shown substantially as shown in Figure 22 Gravimetric analysis vapour system figure.In certain embodiments, after adsorption/desorption analysis, the XRPD patterns of the form I of Formula II Substantially change.In another embodiment, when at about 25 DEG C with about 92% relative humidity store about 7 days, the shape of Formula II Formulas I is converted to form II.In another embodiment, when at about 40 DEG C with about 75% relative humidity store about 7 days, Formula II Form I be converted to form II.In another embodiment, the crystal form I of Formula II has in pH 4.1 is higher than 90mg/ The water solubility of mL.
In certain embodiments, the form I of Formula II can be characterized by grading analysis.In certain embodiments, shape The sample of Formula II includes the particle with birefringent plate lath-like morphologies.In another embodiment, the sample of the form I of Formula II Include the particle of about 100, about 90, about 80, about 70, about 60, about 50, about 40, about 30, about 20, about 10, about 5 μM of length.Certain In embodiment, the sample of the form I of Formula II includes the particle of about 100, about 70, about 60, about 40, about 20, about 10 μM of length. In another embodiment, the sample of the form I of Formula II includes the particle of about 150 μM of length.
In certain embodiments, not less than about 95 weight %, no can be contained by being in the crystal form of the Formula II of form I Less than about 97 weight %, not less than about 98 weight %, not less than about 99 weight % or the not less than about Formula II of 99.5 weight % Salt.The crystal form can also contain not less than about 90 weight %, not less than about 95 weight %, not less than about 98 weight %, The not less than about 99 weight % or crystal form I not less than 99.5 weight %.
Valbenazine dihydrochloride forms II
In another embodiment, be crystal form 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- it is different Butyl -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochloride (Formula II) or its isotopic variations or its solvate；The wherein described crystal form is form II.
In different implementation scenarios, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- bis- The crystalline of methoxyl group -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochlorides (Formula II) Formula II has X-ray diffraction pattern.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- Isobutyl group -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochloride The X-ray diffraction pattern of the form II of (Formula II) is included in the XRP diffraction maximums at about 4.8,13.3 and 24.9 ° of the angles 2- θ. In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxy -2, The X-ray of the form II of 3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochlorides (Formula II) Powder diffraction pattern is included in the XRP diffraction maximums at about 4.8,13.3 or 24.9 ° of the angles 2- θ.In certain embodiments, 2- Amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydros -1H- The X-ray powder diffraction figure sample of the form II of pyrido [2,1-a] isoquinolin-2-yl ester dihydrochloride (Formula II) is included in greatly XRP diffraction maximums at about 4.8 ° of the angles 2- θ.In certain embodiments, 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester The crystalline Formula II of dihydrochloride (Formula II) has X-ray diffraction pattern substantially as shown in Figure 23.
In certain embodiments, the crystalline Formula II of Formula II has one or more in about 4.8 ° and about 24.9 ° The angles 2- θ at characteristic XRP diffraction maximums.In certain embodiments, there is the crystalline Formula II of Formula II one or more to exist Characteristic XRP diffraction maximums at about 4.8 °, about 13.3 ° and about 24.9 ° of the angles 2- θ.In certain embodiments, Formula II Crystalline Formula II have one or more at about 4.8 °, about 13.3 °, about 14.1 ° and about 24.9 ° of the angles 2- θ Characteristic XRP diffraction maximums.In other embodiments, the crystalline Formula II of Formula II have it is one or more about 4.3 °, Characteristic XRP diffraction maximums at about 4.8 °, about 13.3 °, about 14.1 ° and about 24.9 ° of the angles 2- θ.In certain implementations In scheme, the crystalline Formula II of Formula II have it is one or more about 4.3 °, about 4.8 °, about 13.3 °, about 14.1 °, Characteristic XRP diffraction maximums at about 18.4 ° and about 24.9 ° of the angles 2- θ.In other embodiments, the crystalline of Formula II Formula II has one or more at about 4.3 °, about 4.8 °, about 8.7 °, about 13.3 °, about 14.1 °, about 18.4 ° Characteristic XRP diffraction maximums at about 24.9 ° of the angles 2- θ.In other embodiments, the crystalline Formula II of Formula II has one It is a or it is multiple at about 4.3 °, about 4.8 °, about 8.4 °, about 8.7 °, about 13.3 °, about 14.1 °, about 18.4 ° and Characteristic XRP diffraction maximums at about 24.9 ° of the angles 2- θ.In other embodiments, the crystalline Formula II of Formula II has one Or it is multiple about 4.3 °, about 4.8 °, about 8.4 °, about 8.7 °, about 13.3 °, about 14.1 °, about 14.6 °, it is big Characteristic XRP diffraction maximums at about 18.4 ° and about 24.9 ° of the angles 2- θ.
In different implementation scenarios, the crystalline Formula II of Formula II has heat absorption differential scanning calorimetry (DSC) thermogram. In certain embodiments, crystalline Formula II has DSC thermograms, and the figure is with about 80 DEG C of start temperature and about 106 The endothermic event at the peak at DEG C.
In another embodiment, the crystalline Formula II of Formula II is with DSC heat substantially as shown in Figure 24 point Analysis figure.In another embodiment, the crystalline Formula II of Formula II has thermogravimetry (TGA) figure, and it includes work as from about 25 DEG C it is heated to about at 100 DEG C about 10% mass loss.In another embodiment, the crystalline Formula II of Formula II has basic Upper TGA figures as shown in Figure 24.
In different implementation scenarios, the crystalline Formula II of Formula II has gravimetric analysis vapour system (GVS) figure.Certain In embodiment, when the relative humidity for undergoing from about 75% to about 0% relative humidity declines, crystalline Formula II is shown about 12% mass loss.In another embodiment, the crystalline Formula II of Formula II is shown substantially as shown in Figure 25 Gravimetric analysis vapour system figure.In certain embodiments, form II is substantially stable.In another embodiment In, when heated, form II is converted to form I.In another embodiment, when the temperature for being heated above about 160 DEG C, formula The form II of II is converted to amorphous substance.In another embodiment, the crystalline Formula II of Formula II has height in pH 4.1 In the water solubility of 67mg/mL.
In certain embodiments, the form II of Formula II can be characterized by grading analysis.In another embodiment, The sample of the form II of Formula II includes about 100, about 90, about 80, about 70, about 60, about 50, about 40, about 30, about 20, about 10, about 5 μ The particle of M length.In certain embodiments, the sample of the form II of Formula II include about 100, about 70, about 60, about 40, about 20, The particle of about 10 μM of length.
In certain embodiments, be in form II Formula II crystal form can contain not less than about 95 weight %, The Formula II of not less than about 97 weight %, not less than about 98 weight %, not less than about 99 weight % or not less than about 99.5 weight % Salt.The crystal form can also contain not less than about 90 weight %, not less than about 95 weight %, not less than about 98 weights Measure %, not less than about 99 weight % or the crystalline Formula II not less than 99.5 weight %.
In another embodiment, the 2- amino of crystal form -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyls Base -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochloride (formula II) or its isotopic variations or its solvate are amorphous.The amorphous form has substantially such as institute in fig. 26 The X-ray powder diffraction figure sample shown lacks the characteristic XRP diffraction maximums of the particle of the form I and/or form II of Formula II. In one embodiment, the amorphous form of Formula II can contain not less than about 95 weight %, not less than about 97 weight %, not small In about 98 weight %, not less than about 99 weight % or the salt of the not less than about Formula II of 99.5 weight %.The amorphous form is also Can contain not less than about 90 weight %, not less than about 95 weight %, not less than about 98 weight %, not less than about 99 weight % or The amorphous form of Formula II not less than 99.5 weight %.
It should be appreciated that the numerical value at the peak of X-ray powder diffraction figure sample can it is different with random device or different with sample and slightly Variation, thus the value listed be not construed as it is absolute, but with admissible changeability as defined herein, such as 0.2°。
Preparation method
The method for additionally providing the salt of the Formulas I and/or Formula II that are used to prepare amorphous form or crystal form.The method Include the steps that the salt of Formulas I and/or Formula II is made to be contacted with solvent, the wherein particle of the salt of the Formulas I and/or Formula II of amorphous form Or the crystal form (for example, form I, II, III, IV, V or VI) of Formulas I and/or Formula II can be from solution formation or from one kind admittedly Body form is converted to another kind.The method can also include separating step, wherein can by conventional method (such as filtering and Centrifugation) the separation compound, it is then washed with solvent, and then dry (for example, vacuum drying chamber is dry, air-dried or dry Device is dried).
The suitable solvent for being used to prepare the compound of amorphous form or crystal form includes but not limited to：Hydrocarbon, including stone Oily ether, pentane, hexane (class), heptane, octane, isooctane, pentamethylene, hexamethylene, hexahydrotoluene, benzene,toluene,xylene, Naphthane and cumene；Chlorohydrocarbon, including dichloromethane (DCM), 1,2- dichloroethanes, vinylidene chloride, 1,2-dichloroethene, Chloroform, trichloroethanes, trichloro ethylene, carbon tetrachloride, chlorobenzene and trifluoromethylbenzene；Alcohol, including methanol, ethyl alcohol, isopropanol (IPA), 1- propyl alcohol, n-butyl alcohol, 2- butanol, the tert-butyl alcohol, 3- methyl-1-butanols, 1- amylalcohols, 2-methyl cellosolve, 2- ethyoxyls Ethyl alcohol and ethylene glycol；Ether, including ether, Di Iso Propyl Ether, methyl tertiary butyl ether(MTBE) (MTBE), diphenyl ether, 1,2- dimethoxys Ethane, two (2- methoxy ethyls) ethers, 1,1- dimethoxymethane, 2,2- dimethoxy propanes and anisole；Ketone, including third Ketone, butanone, methyl ethyl ketone (MEK), methyl isopropyl Ketone, methyl butyl ketone and methyl iso-butyl ketone (MIBK) (MIBK)；Ester, including second Sour methyl esters, Ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and butyl acetate；Carbonic ester, including Ethylene carbonate and propene carbonate；Amide, including formamide, n,N-Dimethylformamide (DMF) and N, N- dimethylacetamide Amine；Nitrile, including acetonitrile (ACN)；Sulfoxide, such as dimethyl sulfoxide (DMSO)；Sulfone, such as sulfolane；Nitro compound, such as nitro Methane and nitrobenzene；Heterocycle, such as N-Methyl pyrrolidone, 2- methyltetrahydrofurans, tetrahydrofuran (THF), dioxanes and pyrrole Pyridine；Carboxylic acid, such as acetic acid, trichloroacetic acid and trifluoroacetic acid；Phosphamide, such as hexamethyl phosphoramide；Carbon sulfide；Water；And its Mixture.
Using conventional method, including but not limited to cooling, freezing (chilling), evaporation of the solvent or addition anti-solvent can With the salt of solution or slurry preparation Formulas I and/or Formula II in crystal form from the salt of Formulas I and/or Formula II in a solvent Compound.
In one embodiment, the method for being used to prepare the Formulas I of crystal form and/or the salt of Formula II includes following step Suddenly：(a) solution in the first temperature formula I and/or the acid of Formula II in a solvent；(b) crystallization is generated in second temperature Close object.For the formation of accelerating type I and/or the crystal of Formula II, the method can also include before step (b) before or process In to solution sowing form I crystal sowing step.The method can also include that separation as described herein walks Suddenly.
The solution can be prepared from any form of the salt of Formulas I and/or Formula II, and including but not limited to, grease, half are admittedly Or mixtures thereof body, solid (amorphous form or form I, II, III, IV, V or VI of such as Formulas I and/or Formula II).It can be The solution of step (a) is prepared as saturation or close to saturation solution by first temperature.The saturation or close saturation Solution can prepare as follows：The salt of the Formulas I of sufficient amount and/or Formula II is dissolved in institute in the temperature higher than first temperature It states in solvent so that when the solution is cooled to first temperature, solution being saturated or close to saturation.It is based on In solubility of first temperature in the solvent, (it can use people in the art to the compound of Formulas I and/or Formula II Method known to member determines), it can be with the sufficient amount of estimator I and/or the salt of Formula II.
First temperature can be from room temperature to the boiling point of the about described solvent, for example, about 20 DEG C to about 200 DEG C, about 20 DEG C to about 150 DEG C or about 20 DEG C to about 100 DEG C.The second temperature can be -100 DEG C to 100 DEG C, about -50 DEG C to about 50 DEG C, about -10 DEG C to about 30 DEG C, 20 DEG C to about 200 DEG C, about 20 DEG C to about 150 DEG C or about 20 DEG C to about 100 DEG C.First temperature Degree can be higher or lower than or be equal to the second temperature.In order to which the yield and efficiency that make the method maximize, usually by institute Second temperature is stated to be set to be less than first temperature.
In one embodiment, by the second temperature heat the solvent from the solution, formed Formulas I and/ Or the crystalline compounds of Formula II.By applying heat and/or vacuum to the solution, evaporation of the solvent can be promoted.Implement at one In scheme, the solvent is acetonitrile, dichloromethane, DMF ,-dioxane of Isosorbide-5-Nitrae, methanol, 2-methyl cellosolve, MIBK, acetone, 1- Butanol, MTBE, DMSO, ethyl alcohol, ethyl acetate, isobutyl acetate, isopropyl acetate, 1- propyl alcohol, IPA, MEK, THF, water or its Mixture.
In another embodiment, by the way that the solution is cooled to the second temperature, Formulas I and/or Formula II are formed Crystalline compounds.In this case, the second temperature is arranged to be less than first temperature.In an embodiment In, the solvent be acetonitrile, DMF ,-dioxane of Isosorbide-5-Nitrae, methanol, ethyl alcohol, 2-methyl cellosolve, n-butyl alcohol, 1- propyl alcohol, IPA, Or mixtures thereof MIBK, MEK, THF, acetone.In one embodiment, the solvent is acetonitrile, water, 1- propyl alcohol and its mixing Object.In another embodiment, the solvent is acetonitrile, water and its mixture.In another embodiment, the solvent It is 1- propyl alcohol, water and its mixture.In another embodiment, the solvent is 1- propyl alcohol.
In one embodiment, by the way that the solution is cooled to the second temperature, the form I of Formulas I is formed.At this In the case of, the second temperature is arranged to be less than first temperature.In one embodiment, the solvent be acetonitrile/ Water (1%v/v), acetonitrile/water (2%v/v), acetonitrile/water (3%v/v).In one embodiment, the solvent is acetonitrile/water (3%v/v).
In another embodiment, by the way that anti-solvent is added in the solution in second temperature, formed Formulas I and/or The crystalline compounds of Formula II.
Suitable anti-solvent includes but not limited to：Hydrocarbon, including it is petroleum ether, pentane, hexane (class), heptane, octane, different pungent Alkane, pentamethylene, hexamethylene, hexahydrotoluene, benzene,toluene,xylene, naphthane and cumene；Chlorohydrocarbon, including dichloromethane (DCM), 1,2- dichloroethanes, 1,1- dichloroethylene, 1,2- dichloroethylene, chloroform, trichloroethanes, trichloro ethylene, carbon tetrachloride, Chlorobenzene and trifluoromethylbenzene；Alcohol, including methanol, ethyl alcohol, isopropanol (IPA), 1- propyl alcohol, n-butyl alcohol, 2- butanol, the tert-butyl alcohol, 3- Methyl-1-butanol, 1- amylalcohols, 2-methyl cellosolve, cellosolvo and ethylene glycol；Ether, including ether, Di Iso Propyl Ether, Methyl tertiary butyl ether(MTBE) (MTBE), diphenyl ether, 1,2- dimethoxy-ethanes, two (2- methoxy ethyls) ethers, 1,1- dimethoxys Methane, 2,2- dimethoxy propanes and anisole；Ketone, including acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl Ketone, Methyl butyl ketone and methyl iso-butyl ketone (MIBK) (MIBK)；Ester, including methyl acetate, Ethyl formate, ethyl acetate, propyl acetate, second Isopropyl propionate, isobutyl acetate and butyl acetate；Carbonic ester, including ethylene carbonate and propene carbonate；Amide, including formyl Amine, N,N-dimethylformamide (DMF) and DMAC N,N' dimethyl acetamide；Nitrile, including acetonitrile (ACN)；Sulfoxide, such as dimethyl sulfoxide (DMSO)；Sulfone, such as sulfolane；Nitro compound, such as nitromethane and nitrobenzene；Heterocycle, such as N-Methyl pyrrolidone, 2- methyltetrahydrofurans, tetrahydrofuran (THF), dioxanes and pyridine；Carboxylic acid, such as acetic acid, trichloroacetic acid and trifluoroacetic acid；Phosphorus Amide, such as hexamethyl phosphoramide；Carbon sulfide；Water；And its mixture.
When two kinds of solvents are used as solvent/anti-solvent clock synchronization, the compound of Formulas I and/or Formula II have in a solvent than Higher solubility in anti-solvent.Optionally, the solvent of solvent/anti-solvent centering and anti-solvent are miscible at least partly 's.In one embodiment, the solvent is or mixtures thereof acetonitrile, methanol, ethyl alcohol, 1- propyl alcohol, water；And the anti-solvent It is hexane (class), heptane class, ether, ethyl acetate, THF, isopropanol and its mixture.In another embodiment, pass through The solution is added in anti-solvent in second temperature, forms the crystalline compounds of Formulas I and/or Formula II.In an embodiment In, the solvent is or mixtures thereof acetonitrile, methanol, ethyl alcohol, 1- propyl alcohol, water；And the anti-solvent is hexane (class), heptane Class, ether, ethyl acetate, THF, isopropanol and its mixture.
In another embodiment, the method for being used to prepare the crystalline compounds of Formulas I and/or Formula II includes following step Suddenly：(a) slurry in the compound of the first temperature formula I and/or Formula II in a solvent；(b) by the way that the slurry is sudden and violent It is exposed to second temperature and generates formula I and/or the crystalline compounds of Formula II.The slurry can be from the compound of Formulas I and/or Formula II It is prepared by any form, including but not limited to, grease, semisolid, the solid (amorphous form or shape of such as Formulas I and/or Formula II Or mixtures thereof Formulas I, II, III, IV, V or VI).The method can also include as described herein sowing step and/or Separating step.
First temperature and second temperature and the solvent are as defined herein.In one embodiment, described molten Agent is or mixtures thereof acetonitrile, methanol, ethyl alcohol, 1- propyl alcohol, water.
In another embodiment, the method for being used to prepare the crystalline compounds of Formulas I and/or Formula II includes following step Suddenly：(a) solution in the compound of the first temperature formula I and/or Formula II in a solvent；(b) by cooling down the solution To second temperature, slurry is formed；(c) by the way that the slurry is exposed to one or more heating and cooling cycle, formula I is generated And/or the crystalline compounds of Formula II.The method can also include sowing step and/or separating step as described herein.
First temperature and second temperature and the solvent are as defined herein.In one embodiment, described molten Agent is or mixtures thereof acetonitrile, methanol, ethyl alcohol, 1- propyl alcohol, 1,4- dioxanes, water.In one embodiment, the solvent is Water.It is described heating and cooling cycle can about -50 DEG C to about 120 DEG C, about -50 DEG C to about 100 DEG C, about -20 DEG C to about 80 DEG C, About 0 DEG C to about 80 DEG C, about 10 DEG C to about 80 DEG C, about 20 DEG C to about 80 DEG C, about 20 DEG C to about 60 DEG C or about 20 DEG C to about 50 DEG C Temperature range carries out.
In one embodiment, using conventional method, including but not limited to, cooling, freezing, evaporation of the solvent or addition are anti- Solvent, can be from the solution of the compound of Formulas I in a solvent or the form II of slurry formula I.
In one embodiment, the method for being used to prepare the form II of Formulas I includes the following steps：(a) in the first temperature The slurry of the compound of formula I in a solvent；(b) crystalline Formula II is generated in second temperature.In order to accelerate form II's The formation of particle, the method sow the crystal of form II to the solution before or during can also being included in step (b) Sowing step.The method can also include separating step as described herein.
The solution can be prepared from any form of the compound of Formulas I, and including but not limited to, grease, is consolidated semisolid Or mixtures thereof body (amorphous form or form I, II, III, IV, V or VI of such as Formulas I).It can be incited somebody to action in first temperature The solution of step (a) is prepared as saturation or close to saturation solution.The solution of the saturation or close saturation can be as follows It prepares：The compound of the Formulas I of sufficient amount is dissolved in the solvent in the temperature higher than first temperature so that when by institute When stating solution and being cooled to first temperature, solution being saturated or close to saturation.Particle based on form II is described Solubility (it can use method known to those skilled in the art determine) of first temperature in the solvent, can estimate The sufficient amount of the compound of Formulas I.In one embodiment, the solvent is acetonitrile, water and its mixture.In an embodiment party In case, the solvent is water.
In one embodiment, using conventional method, including but not limited to, cooling, freezing, evaporation of the solvent or addition are anti- Solvent, can be from the solution of the compound of Formulas I in a solvent or the form III of slurry formula I.
In another embodiment, the method for being used to prepare the crystalline formula III of Formulas I includes the following steps：(a) The solution of the compound of one temperature formula I in a solvent；(b) by the way that the solution is cooled to second temperature, slurry is formed； (c) by the way that the slurry is exposed to one or more heating and cooling cycle, the crystalline formula III of formula I is generated.The side Method can also include sowing step and/or separating step as described herein.
First temperature and second temperature and the solvent are as defined herein.In one embodiment, described molten Agent is or mixtures thereof acetonitrile, methanol, ethyl alcohol, 1- propyl alcohol, 1,4- dioxanes, water.In one embodiment, the solvent is 1,4- dioxanes/water.In one embodiment, the solvent is water.The heating and cooling cycle can be at about -50 DEG C extremely About 120 DEG C, about -50 DEG C to about 100 DEG C, about -20 DEG C to about 80 DEG C, about 0 DEG C to about 80 DEG C, about 10 DEG C to about 80 DEG C, about 20 DEG C It is carried out to about 80 DEG C, about 20 DEG C to about 60 DEG C or about 20 DEG C to about 50 DEG C of temperature ranges.
In one embodiment, using conventional method, including but not limited to, cooling, freezing, evaporation of the solvent or addition are anti- Solvent, can be from the solution of the compound of Formulas I in a solvent or the form IV of slurry formula I.
In one embodiment, the method for being used to prepare the crystalline formula IV of Formulas I includes the following steps：(a) first The solution of the compound of temperature formula I in a solvent；(b) crystalline compounds are generated in second temperature.In order to accelerating type I's The formation of crystal, the method sow the crystalline substance of form IV to the solution before or during can also being included in step (b) The sowing step of body.The method can also include separating step as described herein.
The solution can be prepared from any form of the salt of Formulas I and/or Formula II, and including but not limited to, grease, half are admittedly Or mixtures thereof body, solid (amorphous form or form I, II, III, IV, V or VI of such as Formulas I and/or Formula II).It can be The solution of step (a) is prepared as saturation or close to saturation solution by first temperature.The saturation or close saturation Solution can prepare as follows：The salt of the Formulas I of sufficient amount and/or Formula II is dissolved in institute in the temperature higher than first temperature It states in solvent so that when the solution is cooled to first temperature, solution being saturated or close to saturation.It is based on In solubility of first temperature in the solvent, (it can use people in the art to the compound of Formulas I and/or Formula II Method known to member determines), it can be with the sufficient amount of estimator I and/or the salt of Formula II.
First temperature can be room temperature to the about described solvent boiling point, for example, about 20 DEG C to about 200 DEG C, about 20 DEG C to about 150 DEG C or about 20 DEG C to about 100 DEG C.The second temperature can be -100 DEG C to 100 DEG C, about -50 DEG C to about 50 DEG C, about -10 DEG C to about 30 DEG C, 20 DEG C to about 200 DEG C, about 20 DEG C to about 150 DEG C or about 20 DEG C to about 100 DEG C.First temperature Degree can be higher or lower than or be equal to the second temperature.In order to which the yield and efficiency that make the method maximize, usually by institute Second temperature is stated to be set to be less than first temperature.
In one embodiment, by the way that the solution is cooled to the second temperature, the form IV of Formulas I is formed. In this case, the second temperature is arranged to be less than first temperature.In one embodiment, the solvent is second Nitrile/water.In one embodiment, the solvent is acetonitrile/water (4%v/v).In one embodiment, the solvent is Acetonitrile/water (10%v/v).
In one embodiment, using conventional method, including but not limited to, cooling, freezing, evaporation of the solvent or addition are anti- Solvent, can be from the solution of the compound of Formulas I in a solvent or the form V of slurry formula I.
In one embodiment, the method for being used to prepare the form V of Formulas I includes the following steps：(a) in the first temperature system The slurry of the compound of standby Formulas I in a solvent；(b) crystal form V is generated in first temperature.In order to accelerate form V's The formation of particle, the method can also be included in step (b) before or during to solution sowing form V crystal Sow step.The method can also include separating step as described herein.
The slurry can be prepared from any form of the compound of Formulas I, and including but not limited to, grease, is consolidated semisolid Or mixtures thereof body (amorphous form or form I, II, III, IV, V or VI of such as Formulas I).It can be incited somebody to action in first temperature The solution of step (a) is prepared as saturation or close to saturation solution.The solution of the saturation or close saturation can be as follows It prepares：The compound of the Formulas I of sufficient amount is dissolved in the solvent in the temperature higher than first temperature so that when by institute When stating solution and being cooled to first temperature, solution being saturated or close to saturation.Particle based on form V is described Solubility (it can use method known to those skilled in the art determine) of one temperature in the solvent, can be with estimator The sufficient amount of the compound of I.In one embodiment, the solvent is acetonitrile, water and its mixture.In an embodiment In, the solvent is water.
In one embodiment, using conventional method, including but not limited to, cooling, freezing, evaporation of the solvent or addition are anti- Solvent, can be from the solution of the compound of Formulas I in a solvent or the form VI of slurry formula I.
In one embodiment, the method for being used to prepare the form VI of Formulas I includes the following steps：(a) in the first temperature The slurry of the compound of formula I in a solvent；(b) crystalline Formula IV is generated in first temperature.In order to accelerate form The formation of the particle of VI, the method can also be included in step (b) before or during to solution sowing form VI's The sowing step of crystal.The method can also include separating step as described herein.
The slurry can be prepared from any form of the compound of Formulas I, and including but not limited to, grease, is consolidated semisolid Or mixtures thereof body (amorphous form or form I, II, III, IV, V or VI of such as Formulas I).It can be incited somebody to action in first temperature The solution of step (a) is prepared as saturation or close to saturation solution.The solution of the saturation or close saturation can be as follows It prepares：The compound of the Formulas I of sufficient amount is dissolved in the solvent in the temperature higher than first temperature so that when by institute When stating solution and being cooled to first temperature, solution being saturated or close to saturation.Particle based on form VI is described Solubility (it can use method known to those skilled in the art determine) of first temperature in the solvent, can estimate The sufficient amount of the compound of Formulas I.In one embodiment, the solvent is acetonitrile, water and its mixture.In an embodiment party In case, the solvent is water.
Using conventional method, including but not limited to, cooling, freezing, evaporation of the solvent or addition anti-solvent can be from Formulas I The amorphous compound of compound solution in a solvent or slurry formula I and/or Formula II.
In one embodiment, the method for being used to prepare the amorphous compound of Formulas I and/or Formula II includes following step Suddenly：(a) solution in the compound of the first temperature formula I and/or Formula II in a solvent；(b) solution is cooled to Two temperature；(c) amorphous compound is generated in the second temperature.The method can also include as described herein Separating step.
The solution can be prepared from any form of the compound of Formulas I and/or Formula II, including but not limited to, grease, Or mixtures thereof semisolid, solid (such as amorphous form or form I, II, III, IV, V or VI).It can be described first The solution of step (a) is prepared as saturation or close to saturation solution by temperature.The solution of the saturation or close saturation can To prepare as follows：The compound of the Formulas I of sufficient amount and/or Formula II is dissolved in the temperature higher than first temperature described molten In agent so that when the solution is cooled to first temperature, solution being saturated or close to saturation.Based on described In solubility of first temperature in the solvent, (it can use well known by persons skilled in the art amorphous compound Method determines), it can be with estimator I and/or the sufficient amount of the compound of Formula II.
In another embodiment, by the way that the solution is cooled to the second temperature, the amorphization is formed Close object.In one embodiment, the solvent is or mixtures thereof alcohol, water.In one embodiment, the solvent is uncle Or mixtures thereof butanol, water.
In another embodiment, described amorphous by will be formed in solution addition anti-solvent in second temperature Compound.The anti-solvent is as defined herein.
In another embodiment, it is used to prepare the method packet of the amorphous compound of the compound of Formulas I and/or Formula II Include following steps：(a) slurry in the compound of the first temperature formula I in a solvent；(b) pass through the phase in second temperature Conversion generates amorphous fine-particle.The slurry can be prepared from any form of the compound of Formulas I and/or Formula II, including but not It is limited to, or mixtures thereof grease, semisolid, solid (such as amorphous form or form I, II, III, IV, V or VI).Institute It states the first temperature and second temperature and the solvent is as defined herein.
Other forming methods (including spray drying, roller drying, desivac and melting crystal) are readily applicable to prepare Crystal form I, II, III, IV, V or VI's and/or Formula II of the Formulas I of amorphous form and/or the compound of Formula II or Formulas I Crystal form I or II.
Pharmaceutical composition
Pharmaceutical composition is also provided herein, it includes be in amorphous form or crystalline as active pharmaceutical ingredient 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxies of Formulas I, II, III, IV, V or VI Base -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) or Its acceptable hydrate or solvate, with one or more pharmaceutically acceptable carriers or excipient composition.
Pharmaceutical composition is also provided herein, it includes be in amorphous form or crystalline as active pharmaceutical ingredient The 2- of Formulas I or II amino -3 Methylbutanoic acid (S)-dimethoxy -2,3,4,6,7 (2R, 3R, 11bR) -3- isobutyl group -9,10-, 11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochloride (Formula II) or its acceptable hydrate or solvent Object is closed, with one or more pharmaceutically acceptable carriers or excipient composition.
The selection of excipient depends greatly on many factors, such as specific method of application, the excipient The property of influence and dosage form to the solubility and stability of the active constituent.
Pharmaceutical composition provided herein can in a unit or multiple dose form provide.List used herein Position dosage form is indicated to be suitable for being administered to humans and animals individual and individually be packed as known in the art physically discrete Unit.Each unit dose contains the active constituent for being enough to generate desired therapeutic effect of predetermined amount and required medicinal Carrier or excipient.The example of unit dosage form includes ampoule, syringe and the tablets and capsules individually packed.It is single Position dosage form can be applied with its part or more parts.Multiple dose form is packed in single container the unit to be detached Multiple identical unit dosage forms of dosage form application.The example of multiple dose form includes bottle, tablet or capsule The bottle of bottle or pint or gallon.
The particle of the compound of Formulas I and/or Formula II provided herein can be administered alone, or with it is provided herein a kind of or A variety of other compounds, one or more other active ingredient combinations applications.Pharmaceutical composition provided herein can be configured to It is a variety of for be administered orally, the dosage form of parenteral administration and local application.Described pharmaceutical composition, which can also be formulated as adjusting, releases agent Type, including delayed release dosage forms, extended release dosage form, Sustained release dosage forms, sustained release forms, pulsed release dosage form, control Release dosage form, acceleration and rapid delivery forms, targeted release dosage form, programmed release dosage form and gastric retention dosage form.These dosage forms It can be prepared (referring to Remington according to conventional method well known by persons skilled in the art and technology:The Science and Practice of Pharmacy, ibid；Modified-Release Drug Delivery Technology, Rathbone et al. is compiled, Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.:New York,NY,2002；Volume 126).
Pharmaceutical composition provided herein can be with single administration or with time interval multiple applications.It should be appreciated that accurate agent The duration of amount and treatment can change with the age of patient being treated, weight and situation, and can use The testing program known empirically is determined by extrapolating from vivo or in vitro experiment or diagnostic data.It further understands, for Any particular individual should adjust tool at any time according to the professional judgement of the personnel of individual need and application or supervision preparation administration Body dosage.
It is administered orally
Pharmaceutical composition provided herein can provide for the solid, semisolid or liquid dosage form of oral administration.This Oral administration used herein further includes the buccal application in oral cavity, tongue application and sublingual administration.Suitable peroral dosage form includes, but not It is limited to, tablet, capsule, pill, lozenge, pastille, pastille, cachet, piller, drug-containing chewing gums, granule, self-contained powder Agent, effervesce or non-effervesce pulvis or granule, solution, emulsion, suspension, solution, wafer, spray agent, elixir And syrup.In addition to the active constituent, described pharmaceutical composition can contain one or more pharmaceutically acceptable carriers Or excipient, including but not limited to, adhesive, filler, diluent, disintegrant, wetting agent, lubricant, glidant, coloring Agent, dye transfer inhibitor, sweetener and corrigent.
Adhesive or granulation agent assign cohesiveness to tablet and keep complete to ensure tablet after compression.Suitable adhesive Or granulation agent includes but not limited to, starch, such as cornstarch, potato starch and pregelatinized starch are (for example, STARCH 1500)；Gelatin；Sugar, such as sucrose, glucose, dextrose, molasses and lactose；Natural and synthesis natural gum, it is such as Arabic Glue, alginic acid, alginate, pelvetia silquosa extract, Pan Waer glue, Indian gum, Chinese herbaceous peony skin mucus, carboxymethyl cellulose, methyl are fine Tie up element, polyvinylpyrrolidone (PVP), aluminium-magnesium silicate, Arabic half poly lactose of larch, tragacanth gum powder and guar gum；It is fine Dimension element, such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyl second Base cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC)；Microcrystalline cellulose, such as AVICEL- PH-101、AVICEL-PH-103、AVICEL RC-581、AVICEL-PH-105(FMC Corp.,Marcus Hook,PA)；And Its mixture.Suitable filler includes but not limited to：Talcum powder, calcium carbonate, microcrystalline cellulose, cellulose powder, glucan Bonding agent, kaolin, mannitol, silicic acid, sorbierite, starch, pregelatinized starch and its mixture.Described adhesive or filling Agent can be present in about 50 weight % to about 99 weight % in pharmaceutical composition provided herein.
Suitable diluent include but not limited to Dicalcium Phosphate, calcium sulfate, lactose, sorbierite, sucrose, inositol, cellulose, Kaolin, mannitol, sodium chloride, dried starch and Icing Sugar end.Certain diluents, such as mannitol, lactose, sorbierite, sucrose and Inositol, in the presence of with sufficient amount, certain compressed tablets can be given, which to assign, to be allowed by chewing the characteristic being disintegrated in mouth.In this way Compressed tablets may be used as chewable tablet.
Suitable disintegrant includes but not limited to：Agar；Soap clay；Cellulose, such as methylcellulose and carboxylic first fiber Element；Timber-work；Natural sponge；Cation-exchange resin；Alginic acid；Natural gum, such as guar gum and aluminium-magnesium silicate HV；Citrus Slurry；Crosslinked cellulose, such as Croscarmellose；Crosslinked polymer, such as Crospovidone；Crosslinked starch；Calcium carbonate； Microcrystalline cellulose, such as primojel；Polacrilin potassium；Starch, such as cornstarch, potato starch, tapioca And pregelatinized starch；Clay；Alginic acid (aligns)；And its mixture.Disintegrant in pharmaceutical composition provided herein Amount change with the type of preparation, and to be those of ordinary skill in the art can easily identify.Pharmaceutical composition provided herein Object can contain the disintegrant of about 0.5 weight % to about 15 weight % or about 1 weight % to about 5 weight %.
Suitable lubricant includes but not limited to：Calcium stearate；Magnesium stearate；Mineral oil；Light mineral oil；Glycerine；Sorb Alcohol；Mannitol；Glycols, such as Compritol 888 ATO and polyethylene glycol (PEG)；Stearic acid；NaLS；Talcum；Hydrogen Change vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil；Zinc stearate；Oil Acetoacetic ester；Ethyl laurate；Agar；Starch；Lycopodium (lycopodium)；Silica or silica gel, such as200 (W.R.Grace Co., Baltimore, MD) and(Cabot Co.of Boston,MA)；And its mixture.Pharmaceutical composition provided herein can contain the profit of about 0.1 weight % to about 5 weight % Lubrication prescription.
Suitable glidant include colloidal silicon dioxide,(Cabot Co.of Boston, MA) and nothing Asbestos talcum.Colorant includes following any：Approved, verified, water-soluble FD＆C dyestuffs, and it is suspended in oxidation FD＆C dyestuffs and color lake and its mixture not soluble in water on aluminium hydrate.Color lake is by the way that water-soluble dye to be adsorbed to The combination that the hydrous oxide of heavy metal is formed to generate the insoluble form of dyestuff.Corrigent include from plant (such as Fruit) extraction natural flavorant, and generate the compound (such as peppermint and gaultherolin) of pleasant sense of taste Synthesis admixture.Sweetener includes sucrose, lactose, mannitol, syrup, glycerine and artificial sweetener, such as saccharin and Ah Si Patan.Suitable emulsifier includes gelatin, Arabic gum, bassora gum, soap clay and surfactant, and such as polyoxyethylene is de- Water sorbitol monooleate（20), Polysorbate 80 80 (80) And Emulphor FM.Suspending agent and dispersant include carmethose, pectin, bassora gum, aluminium-magnesium silicate, Arab Glue, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone.Preservative includes glycerine, para hydroxybenzene first Sour methyl esters and propylparaben, benzoic acid, sodium benzoate and alcohol.Wetting agent includes propylene glycol monostearate, dehydration Sorbitol monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.Solvent includes glycerine, sorbierite, second Alcohol and syrup.The example of the non-aqueous liquid utilized in emulsion includes mineral oil and cottonseed oil.Organic acid include citric acid and Tartaric acid.The source of carbon dioxide includes sodium bicarbonate and sodium carbonate.
It should be appreciated that many carriers and excipient can play several functions in same preparation.Can will herein The pharmaceutical composition of offer is provided as compressed tablets, press back tablet (table triturates), chewable pastille, rapidly dissolving tablet Agent, multiple compressed tablet agent or enteric coated tablet, sweet tablet or film coating tablet.Enteric coated tablet is to use the coated pressure of substance Film-making agent, the effect of the substance tolerance hydrochloric acid in gastric juice but dissolving or disintegration in intestines, to which protection activity ingredient is from the acidity of stomach Environment.Enteric coating agent includes but not limited to aliphatic acid, fat, phenyl salicylate, wax class, lac, ammonification lac and O-phthalic Sour cellulose acetate.Sugar coated tablet is the compressed tablets wrapped up by sugar-coat, and the sugar-coat can help to cover undesirable Taste or smell and protection tablet are from oxidation.Film coating tablet is the pressure covered by the thin layer of water-soluble material or film Film-making agent.Film coating agent includes, but are not limited to hydroxyethyl cellulose, carmethose, Macrogol 4000 and adjacent benzene two Arboxylic acid cellulose.Film coating assigns general features identical with sweet tablet.Multiple compressed tablet agent is by being suppressed more than one Compressed tablets made of cycle, including multilayer tablet and pressed coated tablet or dry coationg tablet.
The Tabules can from the active constituent of powder, crystallization or particle form individually or with one or more Prepare to the carrier of text description or excipient composition, the carrier or excipient include adhesive, disintegrant, controlled release polymer, Lubricant, diluent and/or colorant.Corrigent and sweetener are particularly useful in the formation of chewable tablet and pastille.
Pharmaceutical composition provided herein can be provided as soft or hard capsule, can from gelatin, methylcellulose, Starch or calcium alginate are made.Also referred to as the hard gelatin capsule of dry-filled capsules (DFC) is made of two parts, and a part is sliding It is sleeved on another part, thus encapsulates the active constituent completely.Soft elastic capsules (SEC) are soft spherical shells, such as bright Glue shell is plasticized by adding glycerine, sorbierite or similar polyalcohol.It is micro- to prevent that soft gelatin shell can contain preservative The growth of biology.Suitable preservative be it is as described herein those, including methyl p-hydroxybenzoate and para hydroxybenzene first Propyl propionate and sorbic acid.Liquid, semisolid and solid dosage forms provided herein can be encapsulated into capsule.Suitable liquid Body and semisolid dosage form are included in solution and suspension in propene carbonate, vegetable oil or triglycerides.It can be such as in the U.S. The capsule containing such solution is prepared described in the patent No. 4,328,245,4,409,239 and 4,410,545.Such as this field skill Known to art personnel, capsule can also be coated with to change or keep the dissolving of the active constituent.
Pharmaceutical composition provided herein can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension, Elixir and syrup.Emulsion is binary system, and one of which liquid is dispersed in pellet form in entire another liquid, described Emulsion can be oil-in-water or Water-In-Oil.Emulsion may include pharmaceutically acceptable non-aqueous liquid or solvent, emulsifier and Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Water-alcoholic solutions may include pharmaceutically may be used The acetal of receiving, (term " rudimentary " refers to the alkane for having 1-6 carbon atom to two (low alkyl group) acetals of such as low alkyl group aldehyde Base), for example, acetaldehyde diethyl acetal；And the solvent that water with one or more hydroxyls is miscible, such as propylene glycol and second Alcohol.Elixir is clear, pleasantly sweet and water alcohol solution.Syrup is the concentrated aqueous solution of sugared (for example, sucrose), and may be used also To contain preservative.For liquid dosage form, for example, the solution in polyethylene glycol, can use the pharmaceutically acceptable of sufficient amount Liquid-carrier (for example, water) dilution, easily to measure for applying.
Other useful liquid and semisolid dosage form include but not limited to contain active constituent provided herein and dioxane The mono- or polyalkylene glycol of those of mono- or polyalkylene glycol of base, the dialkylation includes 1,2- dimethoxys Methane, diethylene glycol dimethyl ether, triglyme, tetraethylene glycol dimethyl ether, polyethylene glycol -350- dimethyl ethers, polyethylene glycol - 550- dimethyl ethers, polyethylene glycol -750- dimethyl ethers, wherein 350,550 and 750 indicate that the approximation of the polyethylene glycol is average Molecular weight.These preparations can further include one or more antioxidants, such as Butylated Hydroxytoluene (BHT), anethole htpb (BHA), propylgallate, vitamin E, quinhydrones, Hydroxycoumarin, ethanol amine, lecithin, cephalin, ascorbic acid, apple Acid, sorbierite, phosphoric acid, bisulfites, sodium metabisulfite, thio-2 acid and its ester and aminodithioformic acid Ester.
Pharmaceutical compositions for oral administration provided herein can also be with liposome, micella, microballoon or nanosystems Form provide.It can be as prepared micella dosage form described in U.S. Patent number 6,350,458.
Pharmaceutical composition provided herein can be provided as to non-effervesce or effervesce particle and powder, to be reconstructed into liquid Body dosage form.For in the particle or powder of non-effervesce pharmaceutically acceptable carrier and excipient may include diluent, sweet tea Taste agent and wetting agent.For in the particle or powder of effervesce pharmaceutically acceptable carrier and excipient may include organic acid With carbon dioxide source.
Colorant and corrigent can be used in all above dosage forms.Pharmaceutical composition provided herein can be formulated as Immediate release dosage form adjusts release dosage form, including sustained release form, sustained release form, pulsatile release forms, control release shape Formula, Targeting delivery form and sequencing releasing pattern.
Can by pharmaceutical composition provided herein and will not damage desired therapeutic effect other active constituents or with Supplement substance (such as antacids, proton pump inhibitor and the H of desired effect2Receptor antagonist) it prepares altogether.
It can be by injection, infusion or implantation is parenteral applies pharmaceutical composition provided herein, for part or complete Body is applied.Parenteral administration used herein includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, breastbone Interior, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Parenteral administration
Pharmaceutical composition provided herein can be configured to any dosage form suitable for parenteral administration, including molten Liquid, suspension, emulsion, micella, liposome, microballoon, nanosystems and suitable for before the injection in a liquid wiring solution-forming or The solid form of suspension.Such dosage form can be prepared according to conventional method known to the technical staff in pharmaceutical science field (referring to Remington:The Science and Practice of Pharmacy, ibid).
Be intended for parenteral administration pharmaceutical composition can include one or more pharmaceutically acceptable carriers and Excipient, including but not limited to, aqueous vehicles, water miscible medium, non-aqueous medium, antimicrobial growth Antimicrobial or preservative, stabilizer, chaotropic agent, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and point Powder, wetting agent or emulsifier, complexing agent, screening agent or chelating agent, cryoprotective agent, cryoprotector, thickener, pH are adjusted Agent and inert gas.
Suitable aqueous vehicles include but not limited to water, brine, physiological saline or phosphate buffered saline (PBS) (PBS), chlorine Change sodium injection, ringer's injection, isotonic Dextrose Injection, Sterile Water Injection, dextrose and Lactated Ringer Injection.Non-aqueous medium includes but not limited to fixed oil, castor oil, corn oil, cottonseed oil, the olive of plant origin The middle chain of olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, oil with hydrogenated soybean and coconut oil Triglycerides and palmit seed oil.The miscible medium of water includes but not limited to the poly- second of ethyl alcohol, 1,3 butylene glycol, liquid two Alcohol (for example, Liquid Macrogol and polyethylene glycol 400), propylene glycol, glycerine, n-methyl-2-pyrrolidone, dimethylacetylamide And dimethyl sulfoxide (DMSO).
Suitable antimicrobial or preservative include but not limited to phenol, cresols, mercurial, benzyl alcohol, the tertiary fourth of trichlorine Alcohol, methyl p-hydroxybenzoate and propylparaben, thimerosal, benzalkonium chloride, benzethonium chloride, P-hydroxybenzoic acid first Ester and propylparaben and sorbic acid.Suitable isotonic agent includes but not limited to sodium chloride, glycerine and dextrose.Properly Buffer include but not limited to phosphate and citrate.Suitable antioxidant be it is as described herein those, including Bisulfites and sodium metabisulfite.Suitable local anesthetic includes but not limited to procaine hydrochloride.Suitable suspending Agent and dispersant be it is as described herein those, including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyethylene pyrrole Pyrrolidone.Suitable emulsifier includes those of being described herein, including Tween 20, polyoxy Ethylene dehydrated sorbitol mono-fatty acid ester 80 and Emulphor FM.Suitable screening agent or chelating agent include but not limited to EDTA.Suitable pH adjusting agent includes but not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitable complexing agent include but It is not limited to cyclodextrin, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-beta-cyclodextrin and sulphur butyl Ether 7- beta-cyclodextrins (CyDex,Lenexa,KS)。
Pharmaceutical composition provided herein can be formulated as applying for single dose or multi-dose.The single-dose preparations It is packaged in ampoule, bottle or syringe.The multi-dose parenteral preparation must contain inhibition bacterium or inhibit fungi The antimicrobial of concentration.As known in the art with practice, all parenteral preparations must be sterile.
In one embodiment, described pharmaceutical composition is provided as to the sterile solution of instant.In another implementation In scheme, described pharmaceutical composition is provided as to the soluble products of sterile drying, including freeze dried powder and hypodermic tablets, with It is reconstructed with medium using preceding.In another embodiment, described pharmaceutical composition is provided as the sterile mixed of instant Suspension.In another embodiment, described pharmaceutical composition is provided as to the insoluble product of sterile drying, to use It is preceding to be reconstructed with medium.In another embodiment, by described pharmaceutical composition be provided as instant without bacterial emulsion.
Pharmaceutical composition provided herein can be formulated as to immediate release dosage form or adjust release dosage form, including sustained release shape Formula, sustained release form, pulsatile release forms, control releasing pattern, Targeting delivery form and sequencing releasing pattern.
Described pharmaceutical composition can be formulated as to suspension, solid, semisolid or thixotropic liquid, for as implantation storage Cush is used.In one embodiment, pharmaceutical composition provided herein is dispersed in solid interior matrix, in the solid Portion's matrix is surrounded by outer polymer film, and the polymer film does not dissolve in body fluid, but allows the work in described pharmaceutical composition Property component diffusion passes through.
Suitable internal matrix includes polymethyl methacrylate, polybutyl methacrylate, plasticizing or is not plasticized poly- Vinyl chloride, the polyethylene terephthalate of plasticizing, natural rubber, polyisoprene, polyisobutene, gathers the nylon of plasticizing Butadiene, polyethylene, ethene-vinyl acetate copolymer, silicon rubber, dimethyl silicone polymer, silicone carbonate copolymer, parent Hydrogel, collagen, cross-linking polyvinyl alcohol and the crosslinked partial hydrolysis of the ester of aqueous polymer, such as acrylic acid and methacrylic acid Polyvinyl acetate.
Suitable outer polymer film includes that polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate are total Polymers, ethylene/vinyl acetate, silicon rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second Alkene, the copolymer of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate Ester, butyl rubber, table epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol ternary polymerization Object and ethylene/vinyl ethoxy-ethanol copolymer.
Local application
It can be by pharmaceutical composition provided herein locally application to skin, opening or mucous membrane.Office used herein It includes corium (interior), conjunctiva that portion, which is applied, in cornea, intraocular, eye, ear, transdermal, nose, vagina, urethra, respiratory tract and directly Intestines are applied.
Pharmaceutical composition provided herein can be formulated as suitable for the local application for locally or systemically effect Any dosage form, including emulsion, solution, suspension, cream, gel, hydrogel, ointment, face powder, dressing, elixir, lotion, Suspension, tincture, paste, foam, film, aerosol, irrigation, spray, suppository, bandage, corium patch.It is provided herein The topical formulations of pharmaceutical composition can also include liposome, micella, microballoon, nanosystems and its mixture.
Pharmaceutically acceptable carrier and excipient suitable for topical formulations provided herein include, but are not limited to The miscible medium of aqueous vehicles, water, non-aqueous medium, the antimicrobial of antimicrobial growth or preservative, Stabilizer, chaotropic agent, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and dispersant, wetting agent or emulsification Agent, complexing agent, screening agent or chelating agent, penetration enhancers, cryoprotective agent, cryoprotector, thickener and inert gas.
Described pharmaceutical composition can also local application by the following method：Electroporation, iontophoresis, Ultrasonic penetration are treated Method, phonophoresis and microneedle or Needleless injection, such as POWDERJECTTM(Chiron Corp.,Emeryville, ), and BIOJECT CATM(Bioject Medical Technologies Inc., Tualatin, OR).
Pharmaceutical composition provided herein can be provided in the form of ointment, cream and gelling agent.Suitable ointment Agent medium includes oiliness or hydrocarbon substrate, including such as axunge, adeps benzoinatus, olive oil, cottonseed oil and other oil, white mine Fat；Emulsifiable or absorption base, such as hydrophilic petrolatum, hydroxystearin sulfuric ester and wool grease；Water removable bases, it is all Such as hydrophilic ointment；Water-soluble ointment base includes the polyethylene glycol of different molecular weight；Emulsion bases, Water-In-Oil (W/O) emulsion or Oil-in-water (O/W) emulsion, including cetanol, glycerin monostearate, lanolin and stearic acid are (referring to Remington:The Science and Practice of Pharmacy, ibid).These mediums are softening agents, but usually require to add Add antioxidant and preservative.
Suitable emulsifiable paste matrix can be oil-in-water or Water-In-Oil.Emulsifiable paste medium can be washable and containing oil Phase, emulsifier and water phase.The oil phase is also referred to as "inner" phase, usually by vaseline and fatty alcohol such as cetyl or stearyl alcohol It constitutes.Although not necessarily, the water phase is often more than oil phase in volume, and usually contains moisturizer.In cream preparation Emulsifier can be non-ionic, anion, cationic or both sexes surfactant.
Gel is semisolid suspension type system.Single-phase gels, which contain, to be substantially uniformly distributed in entire liquid-carrier Organic macromolecule.Suitable gelling agent includes crosslinked acrylate copolymer, such as carbomer, carboxyl polyolefin,Hydrophilic polymer, such as polyethylene glycol oxide, Pluronic F68 and polyvinyl alcohol；Cellulosic Polymer, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, phthalic acid hydroxypropyl methyl are fine Dimension element and methylcellulose；Natural gum, such as bassora gum and xanthans；Sodium alginate；And gelatin.In order to prepare uniform gel, Dispersant such as alcohol or glycerine can be added, or gelling agent can be disperseed by grinding, mechanical mixture and/or stirring.
Pharmaceutical composition provided herein can with suppository, pessary, bacillum, application or opoultice, paste, pulvis, apply Material, cream, emplastrum, contraceptive, ointment, solution, emulsion, suspension, tampon, gel, foam, spray or bowel lavage The form rectum of agent, urethra, vagina or perivaginal apply.Using in Remington:The Science and Conventional method described in Practice of Pharmacy (ibid) can prepare these dosage forms.
Rectum, urethra and vaginal suppository are for insertion into the solid of body opening, are at normal temperatures solid, but in body The lower fusing of temperature softens with the discharge active component in opening.The pharmaceutically acceptable load utilized in rectum and vaginal suppository Body includes medium (such as curing agent), is generated when it is prepared with pharmaceutical composition provided herein molten near body temperature Point；With antioxidant as described herein, including bisulfites and sodium metabisulfite.Suitable medium include but Be not limited to, cocoa butter (oleum theobromatis), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, Chinese wax and yellow wax, with And the mono-, di- and glyceryl ester of aliphatic acid properly mix object, hydrogel, such as polyvinyl alcohol, methacrylate, Polyacrylic acid；Glycerinated gelatin.The combination of various kinds of media object can be used.Rectum can be prepared by compression method or molding And vaginal suppository.The typical weight of rectum and vaginal suppository is about 2-3g.
Pharmaceutical composition provided herein can be with solution, suspension, ointment, emulsion, solution, the solution for forming gel It is applied to eye with the form of powder, gel, ophthalmic insert and implantation material.
Pharmaceutical composition provided herein can be intranasally or by being sucked into respiratory tract application.Described pharmaceutical composition can To be provided in the form of aerosol or solution, for using pressurized container, pump, sprayer, atomizer (such as using electric current muscle power Learn generate mist atomizer) sprinkler individually or with suitable propellant (such as 1,1,1,2- tetrafluoroethane or 1,1, 1,2,3,3,3- heptafluoro-propanes) it delivers in combination.Described pharmaceutical composition can also be provided for carrying individually or with inertia The dry powder that body (such as lactose or phosphatide) is blown into combination；And nasal drop.For intranasal use, the powder can include biology Adhesive, including chitosan or cyclodextrin.
Can by for the solution of pressurized container, pump, sprayer, atomizer or sprinkler or suspension be configured to containing： The suitable replacement reagent of ethyl alcohol, hydrous ethanol, or release for disperseing, dissolving or extending active constituent provided herein, Propellant as solvent；And/or surfactant, such as sorbitan trioleate, oleic acid or few lactic acid.
Pharmaceutical composition provided herein can turn to the size for fitting through inhalation delivery with micro mist, such as 50 microns or more Small or 10 microns or smaller.Use breaking method well known by persons skilled in the art, such as spiral spray grinding, fluid bed Jet grinding, supercritical fluid processing, high pressure homogenization or the spray drying for forming nano particle, can prepare this level of Particle.
It can will be configured to containing following substance for the capsule, bubble-cap and cylinder (cartridges) of inhalator or insufflator Mixture of powders：Pharmaceutical composition provided herein；Suitable powdered substrate, such as lactose or starch；And properties modifier, Such as l- leucines, mannitol or magnesium stearate.The lactose can be anhydrous or in the form of monohydrate.It is other suitable Excipient include glucan, glucose, maltose, sorbierite, xylitol, fructose, sucrose and trehalose.For sucking/nose The pharmaceutical composition provided herein of interior application can further include suitable fragrance, such as menthol and Levomenthol, or Sweetener, such as saccharin or saccharin sodium.
It will can be configured to release immediately or adjust to release for the pharmaceutical composition provided herein of local application, including delay Release, sustained release, pulse release, control release, Targeting delivery and sequencing release.
Tune is released
Pharmaceutical composition provided herein can be formulated as adjusting release dosage form.Term " tune is released " used herein indicates this The dosage form of sample：Wherein when being applied by identical approach, the rate of the release of the active constituent or place are different from releasing immediately Put dosage form.It includes that sustained release, extended release, persistently release, sustained release, pulsation or pulse release, control are released to adjust release dosage form It puts, accelerate and quick release, Targeting delivery, sequencing release and gastric retention dosage form.Using well known by persons skilled in the art more Kind adjusts release device and method, and including but not limited to, controlled release base device, infiltration controlled-release device, more granular controlled release devices, ion are handed over Resin, enteric coating, multiple coatings, microballoon, liposome and combination thereof are changed, can be prepared in the pharmaceutical composition for adjusting release dosage form Object.By changing the granularity and polymorphism of the active constituent, the rate of release of the active constituent can also be changed.
Adjust the example released including but not limited to those of described in following U.S. Patent number:3,845,770；3,916, 899；3,536,809；3,598,123；4,008,719；5,674,533；5,059,595；5,591,767；5,120,548；5, 073,543；5,639,476；5,354,556；5,639,480；5,733,566；5,739,108；5,891,474；5,922, 356；5,972,891；5,980,945；5,993,855；6,045,830；6,087,324；6,113,943；6,197,350；6, 248,363；6,264,970；6,267,981；6,376,461；6,419,961；6,589,548；6,613,358；With 6,699, 500。
Controlled release base device
It can be manufactured in the medicine provided herein for adjusting release dosage form using controlled release base device well known by persons skilled in the art Compositions (referring to, Takada et al., " Encyclopedia of Controlled Drug Delivery, " volume 2, Mathiowitz is compiled, Wiley, 1999).
In one embodiment, it is prepared in the medicine group provided herein for adjusting release dosage form using erodible matrix device Object is closed, the erodible matrix device is water-swellable, can lose solution or soluble polymer, includes the polymerization of synthesis Object and naturally occurring polymer and derivative, such as polysaccharide and albumen.
The material that can be used to form erodible matrix includes but is not limited to：Chitin, chitosan, glucan and Pu Lu Blue polysaccharide；Agar, gum arabic, karaya gum, locust bean gum, gum tragacanth, carrageenan, ghatti gum, guar gum, Huang Virgin rubber and scleroglucan；Starch, such as dextrin and maltodextrin；Hydrophilic colloid, such as pectin；Phosphatide, such as lecithin；Seaweed Hydrochlorate；Polyetylene glycol alginate；Gelatin；Collagen；And cellulosic material, such as ethyl cellulose (EC), methylethylcellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), acetylbutyrylcellulose (CAB), CAP, CAT, hydroxypropyl methyl fiber Plain (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose cellulose acetate trimellitate ester (HPMCAT) and ethyl hydroxy ethyl Cellulose (EHEC)；Polyvinylpyrrolidone；Polyvinyl alcohol；Polyvinyl acetate；Fatty acid glyceride；Polyacrylamide；It is poly- Acrylic acid；Ethylacrylic acid or methacrylic acid copolymer (Rohm America,Inc., Piscataway,NJ)；Poly- (2- hydroxyethyls-methacrylate)；Polylactide；Pidolidone and Pidolidone ethyl ester Copolymer；Degradable lactic acid glycolic acid copolymers；Poly- D- (-) -3-hydroxybutyrate；With other acrylic acid derivatives, such as first Base butyl acrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, methacrylic acid (2- dimethylaminos Ethyl) ester and methacrylic acid (trimethylaminoethyl group) ester chloride homopolymer and copolymer.
In another embodiment, the not erodible matrix device of use prepares described pharmaceutical composition.By the activity Ingredient is dissolved or dispersed in inert base, and is mainly discharged by being spread in inert base after application.It is suitable as The material of not erodible matrix device includes but is not limited to：Insoluble plastics, such as polyethylene, polypropylene, poly- isoamyl two Alkene, polyisobutene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, haloflex, polyvinyl chloride, third E pioic acid methyl ester-methylmethacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene/propene copolymer, ethylene/acrylic acid Methacrylate copolymers, the copolymer of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and the poly- terephthaldehyde of propylene, ionomer Sour glycol ester, butyl rubber, table epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol Terpolymer and ethylene/vinyl ethoxy-ethanol copolymer, polyvinyl chloride, the nylon of plasticizing, plasticizing polyethylene terephthaldehyde Acid esters, natural rubber, silicon rubber, dimethyl silicone polymer, silicone carbonate copolymer, and；Hydrophilic polymer, such as ethyl The polyvinyl acetate of cellulose, cellulose acetate, Crospovidone and crosslinked partial hydrolysis；And aliphatic compound, such as Brazil wax, microwax and triglycerides.
In controlled release base system, for example, by using polymer type, polymer viscosity, polymer and/or activity The granularity of ingredient, active constituent, can be with control periods relative to other excipient in the ratio of polymer and the composition The release dynamics of prestige.
By methods known to those skilled in the art, including direct tablet compressing, dry or wet pelletize and then suppress, is molten Change and pelletize and then suppress, can prepare in the pharmaceutical composition provided herein for adjusting release dosage form.
Permeate controlled-release device
It can be manufactured in the pharmaceutical composition provided herein for adjusting release dosage form, the infiltration controlled release using infiltration controlled-release device Device includes a chamber system, two chamber systems, anisotropic membrane technology (AMT) and squeezes out core system (ECS).In general, in this way Device have at least two components：(a) core containing active constituent；(b) it is at least one to encapsulate having for the core The semi-permeable membrane of delivery port.Inflow of the semi-permeable membrane control water from the aqueous environments used to the core, to by passing through The extrusion of the delivery port causes drug release.
In addition to the active constituent, the core of the permeability apparatus optionally includes bleeding agent, and the bleeding agent generates The driving force of water is transported to the core of described device from use environment.A kind of bleeding agent is the hydrophilic polymer of water-swellable, Also referred to as " osmopolymer " and " hydrogel ", including but not limited to, hydrophilic vinyl and acrylate copolymer, polysaccharide Such as calcium alginate, polyethylene glycol oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly- (2- hydroxy ethyl methyl propylene Acid esters), polyacrylic acid, polymethylacrylic acid, polyvinylpyrrolidone (PVP), cross-linked pvp, polyvinyl alcohol (PVA), PVA/PVP The copolymer of copolymer, PVA/PVP and hydrophobic monomer such as methyl methacrylate and vinyl acetate contains big PEO blocks Hdyrophilic polyurethane, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), Hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxy ethyl cellulose (CEC), sodium alginate, poly- card wave Non-, gelatin, xanthans and primojel.
Another kind of bleeding agent is that infiltration is former (osmogen), can be absorbed water to influence the osmotic pressure of across surrounding coating barrier Gradient.Suitably permeating original includes but not limited to：Inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, Potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium sulphate；Sugar, such as dextrose, fructose, grape Sugar, inositol, lactose, maltose, mannitol, gossypose, sorbierite, sucrose, trehalose and xylitol；Organic acid, it is such as anti-bad Hematic acid, benzoic acid, fumaric acid, citric acid, maleic acid, decanedioic acid, sorbic acid, adipic acid, edetic acid(EDTA), glutamic acid, to methylbenzene Sulfonic acid, succinic acid and tartaric acid；Urea；And its mixture.
The bleeding agent of different dissolution rate may be used to influence initially from the speed of the dosage form delivering active ingredients.Example Such as, amorphous sugar such as Mannogeme EZ (SPI Pharma, Lewes, DE) can be used for providing within preceding a few houres very fast Delivering discharges gradually and constantly surplus to maintain to generate desired therapeutic effect immediately within the extended period The treatment or prevention effect of aspiration level.In this case, with such rate discharge active component come substitute metabolism and row The amount for the active constituent let out.
The core can also include a variety of other excipient and carriers as described herein to enhance the dosage form Performance promotes stability or processing.
The material that can be used to form the semi-permeable membrane include the acrylate of various grades, vinyl esters, ether, polyamide, Polyester and cellulosic derivatives are that water is permeable and not soluble in water, or is easy to logical under relevant pH in a physiologically It crosses chemical modification (being such as crosslinked) and assigns water-insoluble.The example that can be used to form the suitable polymer of coating includes plasticizing , cellulose acetate (CA) be not plasticized and enhancing, cellulose diacetate, cellulose triacetate, CA propionic esters, cellulose nitrate Element, acetylbutyrylcellulose (CAB), CA urethanes, CAP, CA methyl carbamate, CA succinates, acetate fiber Plain trimellitic acid ester (CAT), CA dimethylaminoacetates, CA ethyl carbonates, CA chloracetates, CA ethyl oxalates, CA sulphurs Sour methyl esters, CA sulfonic acid butyl ester, CA p-methyl benzenesulfonic acid ester, acetic acid agar, amylose triacetate, beta glucan acetic acid esters, the Portugals β Glycan triacetate, acetaldehyde dimethyl acetate, the triacetate of locust bean gum, the ethene-vinyl acetate of hydration, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, polyacrylic acid and ester and Polymethylacrylic acid and ester and its copolymer, glucan, dextrin, chitosan, collagen, gelatin, polyolefin, polyethers, gather starch Sulfone, polyether sulfone, polystyrene, polyvinylhalide, polyvinylesters and ether, native paraffin and synthetic wax.
Semi-permeable membrane can also be hydrophobic microporous membrane, wherein the hole is substantially filled with a gas and will not be by aqueous Jie Matter soaks, but can pass through water, such as in U.S. Patent number 5, disclosed in 798,119.It is such hydrophobic but water permeatable Film is usually by hydrophobic polymer such as polyolefin, polyethylene, polypropylene, polytetrafluoroethylene (PTFE), polyacrylic acid derivative, polyethers, poly- Sulfone, polyether sulfone, polystyrene, polyvinylhalide, Kynoar, polyvinylesters and ether, native paraffin and synthetic wax composition.
Delivery port on the semi-permeable membrane can be formed by machinery or laser boring after coating.Corrosion can also be passed through Delivery port is formed in situ by the thinner part of the indentation, there of the core ruptures by making the film in water-soluble material plug. Furthermore it is possible to delivery port is formed in coating process, and such as in U.S. Patent number 5,612,059 and 5, the class disclosed in 698,220 In the case of the asymmetric membrane coating of type.
The total amount and rate of release of the active constituent of release can basically by the semi-permeable membrane thickness and porosity, The number of the composition of the core and the delivery port, size and location are adjusted.
Other conventional excipients as described herein can be further included in the pharmaceutical composition of osmotic controlled release dosage form, with Promote performance or the processing of the preparation.
According to conventional method well known by persons skilled in the art and technology can prepare the osmotic controlled release dosage form (referring to, Remington:The Science and Practice of Pharmacy, ibid；Santus and Baker, J.Controlled Release 1995,35,1-21；Verma et al., Drug Development and Industrial Pharmacy 2000,26,695-708；Verma et al., J.Controlled Release 2002,79,7-27).
In certain embodiments, pharmaceutical composition provided herein is formulated as AMT controlled release forms, it includes a kind of non- Symmetrical permeable membrane, the asymmetric permeable membrane coating include the core of the active constituent and other pharmaceutically acceptable excipient The heart.Referring to U.S. Patent number 5,612,059 and WO 2002/17918.According to conventional method well known by persons skilled in the art and Technology, including direct tablet compressing, dry granulation, wet granulation and dip coating method can prepare the AMT controlled release forms.
In some embodiment, pharmaceutical composition provided herein is formulated as ESC controlled release forms, the ESC controlled releases Dosage form includes permeable membrane, and permeable membrane coating is comprising the active constituent, hydroxy ethyl cellulose and other can pharmaceutically connect The core for the excipient received.
More granular controlled release devices
It can be with more granular controlled release device manufacturings in the pharmaceutical composition provided herein for adjusting release dosage form, more particle controls Release device includes a large amount of about 10 μm to about 3mm, about 50 μm to about 2.5mm or about 100 μm to the particle of 1mm diameters, particle or small Ball.By methods known to those skilled in the art, including wet granulation and dry granulation, extrusion/round as a ball, roll, melt-coagulates Knot and spraying seed core, can prepare such more particles.See, e.g., Multiparticulate Oral Drug Delivery；Marcel Dekker:1994；With Pharmaceutical Pelletization Technology；Marcel Dekker:1989。
Can other excipient as described herein be blended with secondary process with described pharmaceutical composition and form institute State more particles.Obtained particle itself may be constructed more particle devices or can be coated with a variety of film forming materials, Such as enteric polymer, water-swellable and water-soluble polymer.More particles can be further processed into capsule or piece Agent.
Targeted delivery
Pharmaceutical composition provided herein can also be configured to target specific tissue, receptor or individual to be treated Other regions of body include based on liposome, based on the red blood cell encapsulated again and based on the delivery system of antibody.Example packet It includes but is not limited to U.S. Patent number 6,316,652；6,274,552；6,271,359；6,253,872；6,139,865；6,131, 570；6,120,751；6,071,495；6,060,082；6,048,736；6,039,975；6,004,534；5,985,307；5, 972,366；5,900,252；5,840,674；5,759,542；With 5,709,874.
Application method
In one embodiment, there is provided herein same with human vesicular monoamine transporter for treating, preventing or improve The method of the related one or more symptoms of inhibition of drum 2 (VMAT2), the method includes giving individual to apply therapeutically effective amount In amorphous form or crystal form I, II, III, IV, V or VI 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester Two (4- toluenesulfonates) (Formulas I)；Or its isotopic variations；Or its solvate.
In another embodiment, there is provided herein for treating, preventing or improving hyperkinesia venereal disease disease The method of one or more symptoms, the method includes being in amorphous form or crystalline using therapeutically effective amount to individual 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxies of Formulas I, II, III, IV, V or VI Base -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I)；Or Its isotopic variations；Or its solvate.
In one embodiment, there is provided herein same with human vesicular monoamine transporter for treating, preventing or improve The method of the related one or more symptoms of inhibition of drum 2 (VMAT2), the method includes giving individual to apply therapeutically effective amount 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups-in amorphous form or crystal form I or II 9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochloride (Formula II)； Or its isotopic variations；Or its solvate.
In another embodiment, there is provided herein for treating, preventing or improving hyperkinesia venereal disease disease The method of one or more symptoms, the method includes being in amorphous form or crystalline using therapeutically effective amount to individual The 2- of Formulas I or II amino -3 Methylbutanoic acid (S)-dimethoxy -2,3,4,6,7 (2R, 3R, 11bR) -3- isobutyl group -9,10-, 11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochloride (Formula II)；Or its isotopic variations；Or its solvent Close object.
In one embodiment, it can including but not limited to be transported with the morbid state that compound described herein is treated Dynamic hyperfunction venereal disease disease such as Huntington disease, tardive dyskinesia, figure rett syndrome, dystonia, hemiballismus, Chorea, senile chorea or twitch.In certain embodiments, the disease shape that can be treated with compound described herein State includes but is not limited to the tardive barrier in the individual with schizophrenia, schizoaffective disorders or mood disorder Hinder.In one embodiment, the morbid state that can be treated with compound described herein includes but is not limited to neural venereal disease Disease or disease, such as bipolar disorder, Major Depressive Disorder, anxiety, Attention deficit hyperactivity disorder, dementia, depression, mistake Dyskinesia, the dyskinesia that dormancy disease, mental disease, posttraumatic stress disorder, substance abuse, Parkinson's disease, levodopa induce Or oppositional defiant disorder.
Dyskinesia includes but is not limited to incoordination, corticobasal degeneration, dyskinesia (paroxysmal), tension mistake Often (generality, segmental, Focal) includes blepharospasm, accessory cramp (neck dystonia), writer's cramp (limbs tension It is not normal), larynx dystonia (spasmophonia) and mouth jaw dystonia, essential tremor, hereditary spastic cut Paralysis, Heng Tingdunshi diseases, multi-system atrophy (Shy Drager syndromes), myoclonia, Parkinson's disease, property fiber crops on progressive core Numbness, restless leg syndrome, rett syndrome, the spasticity caused by apoplexy, cerebral palsy, multiple sclerosis, spinal cord or brain Damage, Sydenham chorea, tardive dyskinesia/dystonia, twitch, figure rett syndrome and Wei Ersenshi diseases.
Depending on the state of disease to be treated and individual, composition provided herein can pass through oral, parenteral (example Such as, intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, hypodermic injection or implantation), it is sucking, nose, vagina, straight Intestines, sublingual or part (such as transdermal or local) administration method application, and can with suitable dosage unit individually or with it is suitable Pharmaceutically acceptable carrier, adjuvant and the medium for closing each administration method are prepared together.It additionally provides provided herein micro- Application of the grain in depot formulation, wherein the active constituent discharges in predetermined time period.
In treatment, prevention or improves hyperkinesia venereal disease disease or inhibit related Other diseases state, disease with VMAT2 In one or more symptoms of disease or disease, dosage level appropriate typically about 0.001-100mg/ kilogram of patient weight/day (mg/kg/ days), about 0.01 to about 80mg/kg/ days, about 0.1 to about 50mg/kg/ days, about 0.5 to about 25mg/kg/ days or about 1 To about 20mg/kg/ days, the dosage can be applied with single dose or multi-dose.Within this range, the dosage can be 0.005-0.05,0.05-0.5 or 0.5-5.0,1-15,1-20 or 1-50mg/kg/ days.In certain embodiments, described dose Amount level is about 0.001-100mg/kg/ days.In certain embodiments, the dosage level is about 0.01 to about 40mg/kg/ It.In certain embodiments, the dosage level is about 0.1 to about 80mg/kg/ days.In certain embodiments, described dose Amount level is about 0.1 to about 50mg/kg/ days.In certain embodiments, the dosage level is about 0.1 to about 40mg/kg/ It.In certain embodiments, the dosage level is about 0.5 to about 80mg/kg/ days.In certain embodiments, described dose Amount level is about 0.5 to about 40mg/kg/ days.In certain embodiments, the dosage level is about 0.5 to about 25mg/kg/ It.In certain embodiments, the dosage level is about 1 to about 80mg/kg/ days.In certain embodiments, the dosage Level is about 1 to about 40mg/kg/ days.In certain embodiments, the dosage level is about 1 to about 25mg/kg/ days.
For being administered orally, described pharmaceutical composition can be provided in the form of tablet, and the tablet contains 1.0-1, 000mg active constituents, particularly from about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 75, about 80, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900 and about 1, 000mg active constituents judge for the symptom of the dosage of patient to be treated.In certain embodiments, the pharmaceutical composition Object can be provided with the tablet form containing about 100mg active constituents.In certain embodiments, described pharmaceutical composition can be with It is provided with the tablet form containing about 80mg active constituents.In certain embodiments, described pharmaceutical composition can be to contain The tablet form of about 50mg active constituents provides.In certain embodiments, described pharmaceutical composition can be to contain about 40mg The tablet form of active constituent provides.In certain embodiments, described pharmaceutical composition can with contain about 25mg activity at The tablet form divided provides.The composition can be applied with scheme one and four times a day, including 1 time a day, 2 times, 3 times and 4 It is secondary.
However, it is to be appreciated that the specific dosage level and administration frequency of any particular patient can be different, this depends on more Kind of factor, including the metabolic stability of the activity of used particular compound, the compound and action time length, the age, Weight, general health, gender, diet, administering mode and time, discharge rate, pharmaceutical composition, disease specific state seriousness With through treated host.
It is also provided herein and adjusts the active methods of VMAT2, the method includes making transport protein and be in one or more The compound of solid form provided herein contacts.In one embodiment, the transport protein is expressed by cell.
Compound provided herein can also with other pharmaceutical agent combinations or be used in combination, other medicaments can be used for controlling Treat, prevent or improve compound provided herein to its useful disease or morbid state (including Huntington disease indicated above, Tardive dyskinesia, figure rett syndrome or twitch) one or more symptoms.In one embodiment, provided herein is Compound can also with other pharmaceutical agent combinations or be used in combination, other medicaments can be used for treating, prevent or improve and essence Refreshing Split disease, schizoaffective disorders, bipolar disorder, Major Depressive Disorder and the other diseases for usually using antipsychotic medications One or more symptoms of the related disease of diseased state or morbid state.
Such other medicaments or drug simultaneously or sequentially can commonly use approach and use with compound provided herein with it Amount application.When particle provided herein and one or more other medicines simultaneously in use, can utilize except containing provided herein is Compound other than also contain the pharmaceutical compositions of such other medicines, but do not require in this way.Therefore, drug provided herein Composition includes the medicine for also containing one or more other active constituents or therapeutic agent in addition to containing compound provided herein Compositions.
Compound provided herein and the weight ratio of second active ingredient can change, and having depending on each ingredient Imitate dosage.In general, the effective dose that each will be used.Thus, for example, when compound provided herein and second of drug or When pharmaceutical composition containing such other medicines is used in combination, the weight ratio of the particle and second of drug can be about 1,000:1 to about 1:1,000 or about 200:1 to about 1:200.The combination of particle provided herein and other active constituents is usual Also each active constituent of effective dose should will be used in aforementioned range, but in each case.
Embodiment
With x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetry (TGA), gravimetric analysis steam It absorbs (GVS), scanning electron microscopy (SEM) and the chromatography of ions (IC) and characterizes Formulas I and/or Formula II in following embodiments Crystalline compounds.
Using Cu K α radiations (40kV, 40mA), θ -2 θ angular instruments and V4 and receive the diverging of slit, Ge monochromators and Lynxeye detectors collect X-ray powder diffraction figure sample on Bruker AXS C2 GADDS diffractometers.Using powdered Material runs sample in room temperature as flat board sample.Sample is gently filled into zero background (510) silicon wafer of incision polishing In cavity.Sample is rotated in the plane of own in the analysis process.With 0.05 degree of 2- θ/rank and 0.5 second/rank from 2 degree Data are collected to 42 degree of 2- θ.
Differential scanning calorimetry is carried out using the Mettler DSC 823E for being equipped with 34 position Autosamplers.In general, The each samples of 0.5-3mg (in pin hole aluminum pot) are heated from 25 DEG C until 250 DEG C with 10 DEG C/min.It is maintained on sample The nitrogen of 50ml/min purges.
Thermogravimetry is carried out on the Mettler TGA/SDTA 851e for being equipped with 34 position Autosamplers.It uses Indium through inspection carries out temperature correction to instrument.Usually by each samples of 5-30mg be loaded on the aluminium crucible weighed in advance and with 10 DEG C/min is heated to 350 DEG C from environment temperature.The nitrogen purging of 50ml/min is maintained on sample.
Gravimetric analysis absorption etc. is obtained using the Hiden IGASorp moisture absorption analyzers controlled by CFRSorp softwares Warm line.Water-bath is recycled by Huber, and sample temperature is maintained 25 DEG C.Pass through the drying of the overall flow rate with 250ml/min The mixed airflow of nitrogen and wet nitrogen controls humidity.Pass through the calibrated Vaisala RH probes (0- near sample The dynamic range of 95%RH) Relative Humidity Measuring (RH).It is continually monitored work by microbalance (accuracy ± 0.001mg) Example weight for the function of %RH changes (quality relaxation).Usually 10-20mg samples are placed at room temperature tared In stainless steel mesh basket.Sample is loaded and unloads 40%RH and 25 DEG C (typical indoor condition).Standerd isotherm is in 0-90%RH It is spaced at 25 DEG C and is carried out with 10%RH in range.
By being coated with desired material (sputtering is coated with) with au film coating and being shown using FEI-Philips XL30 scanning electrons Micro mirror checks it, generates scanning electron micrograph (SEM).The accelerating potential of electronics for analysis is 2.0KV.Use computer The CCD camera attachment of control captures all images.
The chromatography of ions is carried out on 861 Advanced Compact IC sing IC Net softwares v2.3 of Metrohm (IC).The sample of correct amount is prepared as stock solution in solvent soln appropriate, and is suitably diluted before the test. By being compared with the standard solution for the known concentration for being analyzing ion, realize quantitative.
By using Hydranal Coulomat AG reagents and argon gas purging in Mettler Toledo DL39 The karl Fischer (Karl Fisher) measured on Coulometer titrates to measure the water content of each sample.Consolidate what is weighed Body sample is introduced into the container on platinum TGA disks, and the platinum TGA disks are connected to deduction cap (subaseal) and enter to avoid water.Each Titration uses about 10mg samples, and makes duplicate determination.
>=parent the free form of the compound of 10mg/ml is obtained by the way that enough compounds suspend in water Maximum final concentration, determine thermodynamics water solubility.Suspension is balanced 24 hours at 25 DEG C, then measures pH.Then it will mix Suspension is filtered across glass fibre C filters.Then with coefficient appropriate, such as 101, filtrate is diluted.With reference to about 0.25mg/ Standard solution of the ml in DMSO is completed quantitative by HPLC.The standard of injection different volumes, diluted and undiluted sample Product solution.Using calculated by peak area solubility, the peak area passes through in reservation identical with the main peaks in standard injection Between the integral at peak that finds determine.
Embodiment 1
2- amino -3 Methylbutanoic acid (S)-dimethoxy -2,3,4,6,7 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The measurement of the solubility of 11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates)
5 DEG C and 10 DEG C more than the reflux temperature of each solvent, 2- amino -3 Methylbutanoic acid (S)-is carried out from form I (2R, 3R, 11bR) -3- isobutyl groups -9,10- dimethoxys -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinoline Solubility studies in quinoline -2- base esters two (4- toluenesulfonates) (Formulas I) solvent listed by table 1.By form I slurrying at least 2 Hour, then filter.After the mother liquor that evaporation is collected, solubility is calculated by gravimetric analysis.
Embodiment 2
The 2- amino of form I -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The preparation of 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates)
By dimethoxy -1,3 537mg (S) -2- amino -3- metliyl-butyric acids (2R, 3R, 11bR) -3- isobutyl group -9,10-, During 4,6,7,11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl ester free alkali is weighed into vial and it is dissolved in 5mL In MIBK.Then the solution of the p-methyl benzenesulfonic acid of the 1M of 2.56mL (2.0 equivalent) in ethanol is added, obtains clear solution.It gives The solution sows double toluene fulfonates of about 2mg sieving separatings, to which induction crystallizes immediately.Obtained suspension is incubated into 16h, It is spaced between environment temperature and 50 DEG C and is recycled with 4h.After the time, existing solid is isolated by filtration, and under vacuum Dry 3h, to obtain the tiny white solids of 675mg (69%).
The X-ray powder diffraction figure sample of form I is instantiated in Fig. 1.Form I has at about 6.3,17.9 and 19.7 ° The characteristic XRP diffraction maximums that 2- θ are indicated are sentenced, show that the compound is crystalline.As shown in FIG. 4, the particle With regular shape and tablet sample form.
The differential scanning calorimetry thermogram of form I is instantiated in fig. 2.Form I shows to open with about 240 DEG C The endothermic event of beginning temperature and 243 DEG C of peak temperature.
The thermogravimetry thermogram of form I is shown in fig. 2.Form I is highly stable, and is worked as from about 25 It DEG C is heated to about showing the weight saving less than about 0.4% at 140 DEG C.
The gravimetric analysis vapor sorption systems figure of form I is shown in figure 3.When experience from about 0% to about 95% is opposite When the relative humidity of humidity increases, form I shows the quality less than about 1% and increases.
Embodiment 3
The 2- amino of form I -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The recrystallization of 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) is studied
The water (v/v) of 24ml acetonitriles/3% is added into 24.10g forms I.Suspension is heated to 76 DEG C, observes clarification Then it is cooled to 5 DEG C by solution in the case of no sowing with 0.2 DEG C/min.Solid is filtered and in vacuum drying chamber In at 50 DEG C dry 2.5 days I in the form of obtaining 72%, the characteristic XRPD with Fig. 1.
In another experiment, 8ml 1- propyl alcohol (5.3 volume) is added into 1.50g forms I.Suspension is added at 88 DEG C Heat observes clear solution, it is then cooled to 5 DEG C in the case of no sowing with 0.5 DEG C/min.Simultaneously by solid filtering 2.5 days I in the form of obtaining 88%, the characteristic XRPD with Fig. 1 are dried at 50 DEG C in vacuum drying chamber.
In general, using acetonitrile/3% water (v/v) or 1- propyl alcohol of 10 volumes, form I can be successfully recrystallized.When Amount using water when acetonitrile is critical：3% water is needed to obtain the good dissolving degree of the substance, but 4% water can It can lead to form IV.
Embodiment 4
The 2- amino of form I -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) in aqueous solution and Solubility in organic solvent
By the 2- amino of 100mg forms I -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxies Base -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) are weighed into glass In glass bottle, and the related aqueous mediums of 1ml are added.Shake bottle.After 1 hour, via syringe take out sample (~ 0.5ml), and across (0.2 micron) filtering of syringe filter enter in second bottle.Then by 200 μ l each solution turn HPLC bottles of shift-in simultaneously complements to 1ml by the way that 800 μ l diluents are added.These samples are directly analyzed by HPLC, and response exists Outside the range of linearity.Therefore, it carries out second to dilute, takes each samples of 0.1ml and complement to 2ml with diluent.Sample is passed through HPLC is reanalysed.Then, after suspension shake is 18 hours total, second sample is taken out as described above.Then, such as It is upper described, all samples are diluted and are analyzed by HPLC.Temperature (22 DEG C) is recorded, gelling is not observed.
Form I (1.2-6.8) within the scope of the pH of experiment shows very consistent and very high solubility.It Somewhat higher when pH 1.2 and pH 6.8.
It repeats above operation, but (is only divided after 18 hours using 8 kinds of different organic solvent instead of water media Analysis).The solvent used is acetonitrile, ether, ethyl alcohol, ethyl acetate, isopropanol, methanol, heptane and THF.In addition to 100mg is dissolved Other than methanol in 0.3ml, all solvents generate suspension in 100mg/ml.Therefore, first is added in additional 70mg forms I Alcohol bottle is to generate suspension.After slurrying in 18 hours, these experiments are sampled.As a result it is reported in Table 3.
Embodiment 5
The 2- amino of form I -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The granulometry of 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates)
Using isooctane as the dispersant of experiment, Malvern Mastersizer MicroPlus Analyzer are used (Malvern Instruments, UK) measures the average particle size and size distribution of the particle in form I.The equipment is warmed About 1 hour, and sample dispersion unit is added in about 100ml dispersants.Dispersant is used to measure background first.By will~ 100mg forms I, which is added into 2ml dispersants, prepares fresh sample, and by its sonication~5 minute.It is being dispersed with stirring the same of agent When sample is added dropwise in sample dispersion unit, until realizing suitable shading value (obscuration value) (that is, 16- 25%), and size distribution can be measured.It does for each sample and at least measures three times.
The 2- amino of form I -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The size distribution (PSD) of 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) As a result it may refer to table 4.These are the values selected from repeated measuring results.
Embodiment 6
The 2- amino of form I -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The stability study of 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates)
By the 2- amino of two batches form I -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- diformazans Oxygroup -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) are long-term 60 months duration are placed with intermediate time scale storage condition and are placed 6 months duration under the conditions of accelerated storage, it is steady to study It is qualitative.The storage requirement includes long-term storage requirement, the mid-term of 30 ± 2 DEG C/65 ± 5%RH of 25 ± 2 DEG C/60 ± 5%RH The accelerated storage condition of storage requirement and 40 ± 2 DEG C/75 ± 5%RH.Stability result is reported in Table 5.
Two batches form I until 3 months stability data present in table 5.The acceleration of these batches and steady in a long-term The result of Journal of Sex Research confirms, when storing up to 3 months under the long-term storage requirement in 25 DEG C/60%RH and 40 DEG C/75% When being stored 3 months under the conditions of the accelerated storage of RH, the chemically and physically stability of form I.
Table 1. for each solvent, at less than the 5 of reflux DEG C and 10 DEG C the Formulas I of form I solubility
The water solubility of 2. form I of table
The solubility of 3. form I of table in organic solvent
The size distribution of 4. form I of table
The stability data of 5. 3 crowdes of form I of table
The recrystallization of 6. form I of table is studied
Embodiment 7
The 2- amino of form II -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The preparation of 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates)
By 186mg unbodied 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxies Base -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) are 3 Slurrying is stayed overnight (4h hot/colds recycle, between room temperature and 50 DEG C) in the water of volume.Obtain white crystals thing and in vacuum drying chamber In in 40 DEG C of dry 4h.
The X-ray powder diffraction figure sample of form II is instantiated in Figure 5.Form II has in about 5.7,15.3 and The characteristic XRP diffraction maximums indicated with 2- θ at 22.5 ° show that the compound is the crystal form (form different from form I II)。
The differential scanning calorimetry thermogram of form II is instantiated in Figure 5.Form II is shown with about 143 DEG C The endothermic event of start temperature and 155 DEG C of peak temperature.
Embodiment 8
The 2- amino of form III -3 Methylbutanoic acid (S)-dimethoxy -2 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The preparation of 3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates)
Make 100mg unbodied 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxies Base -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) exist 95:Maturation 72h in 5-dioxanes of Isosorbide-5-Nitrae/water recycles between environment temperature and 50 DEG C per 4h, obtains solid.By the solid It is isolated by filtration and 3h is dried under vacuum.
The X-ray powder diffraction figure sample of form III is instantiated in fig. 8.Form III has about 6.3,18.3, 18.9, the characteristic XRP diffraction maximums indicated with 2- θ at 19.8 and 20.4 ° show that the compound is different from form I or II Crystal form (form III).
The differential scanning calorimetry thermogram of form III is instantiated in fig.9.Form III show about 93 DEG C, about 158 DEG C and about 230 DEG C of endothermic event temperature.
Embodiment 9
The 2- amino of form IV -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The preparation of 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates)
By 2- amino -3 Methylbutanoic acid (S)-dimethoxy -2 (2R, 3R, 11bR) -3- isobutyl group -9,10- at 71 DEG C, 3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) (500mg) It is dissolved in the water of 1.0ml acetonitriles/10%.Then clear solution is cooled to 5 DEG C with 10 DEG C/h.Solid is filtered and 30 It DEG C is dried under vacuum 1.5 hours.
The X-ray powder diffraction figure sample of form IV is instantiated in Fig. 10.Form IV has about 6.2,10.4, 17.9, the characteristic XRP diffraction maximums indicated with 2- θ at 19.2,19.9 and 20.2 ° show that the compound is different from form I, the crystal form (form IV) of II or III.
The differential scanning calorimetry thermogram of form IV is instantiated in fig. 11.Form IV show about 128 DEG C, about 159 DEG C and about 237 DEG C of endothermic event temperature.
Embodiment 10
The 2- amino of form V -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The preparation of 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates)
By 1.41g unbodied 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxies Base -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) exist Slurrying 4 hours in 5ml water.By white crystals thing filtering and drying.Retain mother liquor.After 48h, crystalline needles are from mother liquor It is precipitated out.By the particle in drying at room temperature 2h in vacuum drying chamber.
The X-ray powder diffraction figure sample of form V is instantiated in fig. 13.Form V has about 6.7,7.9,10.7, 12.8, the characteristic XRP diffraction maximums indicated with 2- θ at 17.1 and 23.7 °, show the compound be different from form I, II, The crystal form (form V) of III or IV.
The differential scanning calorimetry thermogram of form V is instantiated in fig. 14.Form V shows about 113 DEG C and about 181 DEG C endothermic event temperature.
Embodiment 11
The 2- amino of form VI -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The preparation of 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates)
By 1.41g unbodied 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxies Base -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) exist Slurrying 4 hours in 5ml water.White crystals thing is filtered and is dried overnight at 40 DEG C in vacuum drying chamber.
The X-ray powder diffraction figure sample of form VI is instantiated in figure 16.Form VI has about 6.8,8.0,16.3 With 17.5 ° at the characteristic XRP diffraction maximums that are indicated with 2- θ, show that the compound is different from form I, II, III, IV or V Crystal form (form VI).
The differential scanning calorimetry thermogram of form VI is instantiated in fig. 17.Form VI shows about 175 DEG C and about 238 DEG C endothermic event temperature.
Embodiment 12
Balancing each other between form I, II and IV of Formulas I
Form I (80mg), form II (50mg) and form IV (20mg) are mixed.It then will about 10mg mixtures Slurrying 13 days at the desired temperatures in the 200 pre-saturated solvents of μ l.Then solid is rapidly filtered and is divided by XRPD Analysis.
It was found that form IV is at 5 DEG C for acetonitrile/water>The thermodynamic product of 2% mixture.At 25 DEG C, only observe To form I.As a result it is summarised in table 7.
Embodiment 13
Balancing each other between the form I and IV of Formulas I
The suspension of form I and IV from balance studies is set to reach 25 DEG C.Form IV is not converted after being stirred overnight. Then heat the sample to 30 DEG C keep 2 days, to form I conversion then terminate.As a result it is reported in Table 8.
Balance studies between table 6. form I, II and IV
Balance studies between the form I and IV of 7. Formulas I of table
(overnight) is heated at 30 DEG C to observe later XRPD results (2 days) are heated at 30 DEG C to observe later XRPD results
White depositions The form I of form IV+ traces White depositions Form I
White depositions Form IV White depositions Form I
White depositions Form IV White depositions Form I
White depositions Form IV White depositions Form I
White depositions Form IV White depositions Form I
The X-ray powder diffraction of the form I of 8. Formulas I of table
The X-ray powder diffraction of the form II of 9. Formulas I of table
The X-ray powder diffraction of the form III of 10. Formulas I of table
The X-ray powder diffraction of the form IV of 11. Formulas I of table
The X-ray powder diffraction of the form V of 12. Formulas I of table
The X-ray powder diffraction of the form VI of 13. Formulas I of table
Embodiment 14
The 2- amino of form I -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The preparation of 4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochlorides (Formula II)
To (2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyridos [2, 1-a] NaOH of 0.5M is added in suspension of the isoquinolin -2- alkoxide (32.3g, 58.54mmol) in dichloromethane (300mL) Aqueous solution (150mL).By organic layer separation, it is used in combination water (50mL) to wash, and then through Na2SO4It is dry.Organic layer is filtered, and DMAP (1.79g, 0.25 equivalent, 14.63mmol) and Boc-L-Val-OH is added into obtained mixture, and (15.26g, 1.2 work as Amount, 70.25mmol).Reaction mixture is cooled to -10 DEG C, EDC (16.83g, 1.5 equivalents, 87.81mmol) is added, and will Obtained mixture stirs 3 hours.The Boc-L-Val-OH (2.54g) and 0.25 that 0.2 equivalent is added into the mixture works as The EDC (2.8g) of amount.After stirring 1.5 hours, water (50mL) is added, 5% aqueous citric acid solution is used in combination in organic layer separation (2x 100mL) is washed.Combined organic extract is washed with water (100mL), and then through Na2SO4It is dry.By organic layer mistake It filters and dries.
Crude object is put into dichloromethane and is cooled to 5 DEG C.It is added in the HCl dioxanes of 4M into the mixture Solution (64.37mL, 4.4 equivalents, 257.50mmol).The solution in the HCl dioxanes of other 20mL 4M is added.5 is small Reaction mixture is cooled to 10 DEG C and 8% NaHCO is added by Shi Yihou3Aqueous solution (700mL).By organic layer separation and incite somebody to action Water layer is extracted with dichloromethane (100mL).Combined organic extract is washed with water, and then through Na2SO4Dry, filtering is simultaneously It is concentrated under vacuum to obtain residue.Acetonitrile is added into residue, and by the 3.5N's of 2.1 equivalents of obtained mixture Solution of the HCl in IPA is handled at 5 DEG C.Reaction mixture is warmed to room temperature.EtOAc is added, and heats the mixture to 50 DEG C and sowing 165mg 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4, 6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochloride.After stirring 30min at 50 DEG C, it is added more More EtOAc, and mixture is flowed back 1h.Heating is removed, and brings the mixture to room temperature.Solid by filtration is taken out and is used in combination EtOAc is washed to obtain 15.4g 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxies Base -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochloride.
The X-ray powder diffraction figure sample of form I is instantiated in fig. 20.Form I has at about 7.2,9.2 and 18.0 ° The characteristic XRP diffraction maximums that 2- θ are indicated are sentenced, show that the compound is crystal form (form I).When experience from about 0% to When the relative humidity of about 90% relative humidity increases, the quality that heat analysis shows about 14% increases.In 25 DEG C/92%RH and 40 DEG C/the 75%RH storage changes for all causing form in 7 days.Water solubility is evaluated as>The free form in pH 4.1 of 90mg/mL Equivalent.
Embodiment 15
The 2- amino of form II -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, The preparation of 4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochlorides (Formula II)
By by the 2- amino of 200mg forms I -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl groups -9,10- two Methoxyl group -2,3,4,6,7,11b- hexahydro -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochlorides (Formula II) are in service plate It sprawls straticulation and exposes the samples to the environment 72h of 25 DEG C/75%RH, prepare form II.
The X-ray powder diffraction figure sample of form II is instantiated in fig. 24.Form II has in about 4.8,13.3 and The characteristic XRP diffraction maximums indicated with 2- θ at 24.9 ° show that the compound is the crystal form (form different from form I II).Heat analysis shows 10.4% mass loss, and water content is determined as 13.9%m/m by Karl Fisher analysis.By water dissolution Degree is evaluated as>The free form equivalent in pH 4.1 of 67mg/mL.
VT-XRPD research shows that be not converted into form I when heated；The substance becomes in about 160 DEG C or more of temperature At unbodied, do not crystallize while cooling then.GVS analysis shows, when RH is reduced to 0%, the substance loses it Quality about 12%.Do not know form change whether with the water loss, because of the water when sample is back to environment RH It can easily suck back.
The X-ray powder diffraction of the form I of 14. Formula II of table
The X-ray powder diffraction of the form II of 15. Formula II of table
Embodiment 16
Unbodied 2- amino -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester two (4- toluenesulfonates) (Formulas I) and 2- amino - 3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyridines And the preparation of [2,1-a] isoquinolin-2-yl ester dihydrochloride (Formula II)
By dimethoxy -2 about 15mg 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10-, 3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester two (4- toluenesulfonates) (Formulas I) and 2- ammonia Base -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrroles Simultaneously [2,1-a] isoquinolin-2-yl ester dihydrochloride (Formula II) is respectively dissolved in the 2 of 2mL for pyridine:1tBuOH:In water.It is clear by what is obtained Clear solution is rapidly frozen in dry ice/acetone batch, and is lyophilized into fluffy white solid.XRPD is analysis shows the object being freeze-dried Matter is amorphous in each case, and1H NMR confirm that various counter ion counterionsl gegenions still have.
Embodiment 17
Unbodied 2- amino -3 Methylbutanoic acid (S)-dimethoxy -2,3 (2R, 3R, 11bR) -3- isobutyl group -9,10-, 4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls ester two (4- toluenesulfonates) (Formulas I) and 2- amino - 3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyridines And the ripe array (maturation array) of [2,1-a] isoquinolin-2-yl ester dihydrochloride (Formula II)
By the unbodied 2- amino of about 50mg -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- diformazans Oxygroup -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yls esters two (4- toluenesulfonates) (Formulas I) With 2- amino -3 Methylbutanoic acid (S)-(2R, 3R, 11bR) -3- isobutyl group -9,10- dimethoxys -2,3,4,6,7,11b- six Hydrogen -1H- pyridos [2,1-a] isoquinolin-2-yl ester dihydrochloride (Formula II) is weighed into each bottle in 48 bottles. Enough specified solvents are added to form slurry, and bottle is incubated into 72h, per 4h between environment temperature and 50 DEG C Cycle.Any solid by filtration separation existing for the point, and analyzed by XRPD.The experiment of not solid is removed into cap simultaneously Allow to be nucleated；These all without providing any crystal, all generate the colloid (gum) of viscosity.As a result it is shown in table 16.
Ripe array on the amorphous salt of 16. Formulas I of table and Formula II
Embodiment 18
(S) dimethoxy-1,3,4,6,7-2- amino-3- metliyl-butyric acids (2R, 3R, 11bR)-3- isobutyl group-9,10-, The counter ion counterionsl gegenions of 11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl ester screen
By dimethoxy -1 about 50mg (S) -2- amino -3- metliyl-butyric acids (2R, 3R, 11bR) -3- isobutyl group -9,10-, 3,4,6,7,11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl ester free alkali is weighed into every in 54 HPLC bottles In one.Then the related solvents of 500 μ L are added into each, and bottle is shaken into 1h in room temperature, in all cases To clear solution.Then each experiment is added in the related acid of 2.0 equivalents.Then bottle is put into 16h in the incubator, existed per 4h It is recycled between environment temperature and 50 DEG C.Any visible solid is filtered out and is analyzed by XRPD.Contain the small of colloid by any Bottle incubates other 60h, which detaches any solid by filtration and characterized by XRPD later.
Embodiment 19
(S) dimethoxy-1,3,4,6,7-2- amino-3- metliyl-butyric acids (2R, 3R, 11bR)-3- isobutyl group-9,10-, The counter ion counterionsl gegenions screening that the anti-solvent of 11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl ester mediates
By dimethoxy -1 about 50mg (S) -2- amino -3- metliyl-butyric acids (2R, 3R, 11bR) -3- isobutyl group -9,10-, 3,4,6,7,11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl ester free alkali is weighed into every in 27 reaction tubes In one.500 μ L acetonitriles are added into 18 in these, to 500 μ L 99 are added in other 9:1 acetonitrile/water.Then with The related acid of 2.1 equivalents is added in available most conc forms.Under constant stirring, each examination is added in enough ethyl acetate The test tube is heated to 50 DEG C of holding 1h by pipe to cause muddiness, is then cooled to room temperature.By any existing solid It filters out and is analyzed by XRPD.In addition to regenerate the crystalline salt form of p-methyl benzenesulfonic acid and oxalic acid detached in embodiment 18 with Outside, new crystalline hydrobromate and mesylate are identified, and with the diffraction different from previously observed pattern The benzene sulfonate of pattern.The dsc analysis of the new benzenesulfonate salt forms shows the endothermic event of early stage, is followed by and significantly ties again Brilliant and then fusing.As a result it is shown in table 17.
The result for the counter ion counterionsl gegenions screening that table 17. is mediated from anti-solvent
Embodiment 20
(S) dimethoxy-1,3,4,6,7-2- amino-3- metliyl-butyric acids (2R, 3R, 11bR)-3- isobutyl group-9,10-, 11b- hexahydro -2H- pyridos [2, l-a] isoquinolin-2-yl ester from anti-solvent mediate counter ion counterionsl gegenions screening salt it is more Crystalline form is assessed
The related salt forms of about 10mg are suspended in the specified solvents of 100 μ L.Then suspension is incubated into 72h, existed per 4h It is recycled between environment temperature and 50 DEG C.After being cooled to room temperature, any existing solid is filtered out and is analyzed by XRPD.As a result it shows Show in table 18.
The result of 18. polymorphic of table assessment
Although all salt all notices the diffraction pattern (label is new pattern in upper table) with additional peak, But definitely identify new model for the hydrobromate detached from MIBK and DCM.In other cases, the substance is mainly Same form in input experiment, there is some other peaks to exist.
The summary for the salt that table 19. is formed
The salt of all formation is all shown and the comparable binary Chemical Measurement of input substance and purity.
There is provided above-described embodiment come to those of ordinary skill in the art provide complete disclosure and how to realize and Using the description of the embodiment, it is not intended to limit the scope of the disclosure.To those skilled in the art show and The modification of above-mentioned pattern being clear to, for realizing present disclosure is intended that within the scope of the following claims.In this theory The all publications, patents and patent applications quoted in bright book are all incorporated herein by reference, as specifically and individually referred to Go out and every such publication, patent or patent application are incorporated herein by reference.

Claims (107)

1. the crystal form I of the compound of Formulas I：
2. crystal form as described in claim 1 has one be included at about 6.3,17.9 and 19.7 degree of ± 0.2 θ of 2- θ The X-ray powder diffraction figure sample at a or multiple peaks.
3. crystal form as claimed in claim 1 or 2 has X-ray powder diffraction substantially as shown in FIG. 1 Pattern.
4. the crystal form as described in any one of claim 1-3, described with differential scanning calorimetry thermogram Differential scanning calorimetry thermogram includes the endothermic event with about 240 DEG C of start temperature and the peak at about 243 DEG C.
5. there is the crystal form as described in any one of claim 1-4 differential substantially as shown in Figure 2 to sweep Retouch calorimetry thermogram.
6. the crystal form as described in any one of claim 1-5, have comprising when being heated to about 140 DEG C from about 25 DEG C When mass loss less than about 0.4% thermogravimetry figure.
7. the crystal form as described in any one of claim 1-6 has thermogravimetric amount substantially as shown in Figure 2 Analysis chart.
8. the crystal form as described in any one of claim 1-7, when being exposed to about 25 DEG C and about 60% relative humidity about 3 A month, be stable.
9. the crystal form as described in any one of claim 1-8, when being exposed to about 25 DEG C and about 92% relative humidity, It is stable.
10. the crystal form as described in any one of claim 1-9, when being exposed to about 40 DEG C and about 75% relative humidity about 3 months, be stable.
11. the crystal form as described in any one of claim 1-10, when it undergoes from about 0% to about 95% relative humidity Relative humidity increase when, show about 1% quality increase.
12. the crystal form as described in any one of claim 1-11 shows substantially to weigh as shown in Figure 3 Amount analysis vapour system figure.
13. the crystal form as described in any one of claim 1-12, wherein the form contains not less than about 90 weights Measure %, not less than about 95 weight %, not less than about 98 weight %, not less than about 99 weight % or the knot not less than 99.5 weight % Crystalline form I.
14. the crystalline Formula II of the compound of Formulas I：
15. crystal form as claimed in claim 14 has and is included at about 5.7,15.3 and 22.5 degree of ± 0.2 θ of 2- θ The X-ray powder diffraction figure sample at one or more peaks.
16. the crystal form as described in any one of claims 14 or 15 has X- substantially as shown in FIG. 5 Ray powder diffraction pattern.
17. the crystal form as described in any one of claim 14-16, with differential scanning calorimetry thermogram, The differential scanning calorimetry thermogram includes the heat absorption thing with about 143 DEG C of start temperature and the peak at about 155 DEG C Part and another endothermic event with about 232 DEG C of start temperature and the peak at about 235 DEG C.
18. the crystal form as described in any one of claim 14-17 has difference substantially as shown in FIG. 6 Show scanning calorimetry thermogram.
19. the crystal form as described in any one of claim 14-18, have comprising when being heated to about from about 25 DEG C The thermogravimetry figure of about 2.2% mass loss at 140 DEG C.
20. the crystal form as described in any one of claim 14-19 has heat substantially as shown in FIG. 6 Gravimetric analysis figure.
21. the crystal form as described in any one of claim 14-20, when its experience is relatively wet from about 0% to about 95% When the relative humidity of degree increases, about 0.5% quality increase is shown.
22. the crystal form as described in any one of claim 14-21 is shown substantially as shown in FIG. 7 Gravimetric analysis vapour system figure.
23. the crystal form as described in any one of claim 14-22, wherein the form contains not less than about 90 weights Measure %, not less than about 95 weight %, not less than about 98 weight %, not less than about 99 weight % or the knot not less than 99.5 weight % Crystalline form II.
24. the crystalline formula III of the compound of Formulas I：
25. crystal form as claimed in claim 24 has and is included in about 6.3,18.3,18.9,19.8 and 20.4 degree of 2- θ The X-ray powder diffraction figure sample at one or more peaks at ± 0.2 θ.
26. the crystal form as described in any one of claim 24 or 25 has X- substantially as shown in FIG. 8 Ray powder diffraction pattern.
27. the crystal form as described in any one of claim 24-26, with differential scanning calorimetry thermogram, The differential scanning calorimetry thermogram includes the endothermic event with about 93 DEG C, about 158 DEG C and about 230 DEG C of temperature.
28. the crystal form as described in any one of claim 24-27 has difference substantially as shown in FIG. 9 Show scanning calorimetry thermogram.
29. the crystal form as described in any one of claim 24-28, have comprising when being heated to about from about 25 DEG C The thermogravimetry figure of about 2.7% and about 8.86% two kinds of mass losses at 140 DEG C.
30. the crystal form as described in any one of claim 24-29 has heat substantially as shown in FIG. 9 Gravimetric analysis figure.
31. the crystal form as described in any one of claim 24-29, wherein the form contains not less than about 90 weights Measure %, not less than about 95 weight %, not less than about 98 weight %, not less than about 99 weight % or the knot not less than 99.5 weight % Crystalline form III.
32. the crystalline formula IV of the compound of Formulas I：
33. crystal form as claimed in claim 32 has and is included in about 6.2,10.4,17.9,19.2,19.9 and 20.2 Spend the X-ray powder diffraction figure sample at one or more peaks at ± 0.2 θ of 2- θ.
34. the crystal form as described in any one of claim 32 or 33 has substantially as shown in Figure 10 X-ray powder diffraction figure sample.
35. the crystal form as described in any one of claim 32-34, with differential scanning calorimetry thermogram, The differential scanning calorimetry thermogram includes the endothermic event with about 128 DEG C, about 159 DEG C and about 237 DEG C of temperature.
36. the crystal form as described in any one of claim 32-35 has difference substantially as shown in Figure 11 Show scanning calorimetry thermogram.
37. the crystal form as described in any one of claim 32-36, have comprising when being heated to about from about 25 DEG C The thermogravimetry figure of about 3.3% mass loss at 140 DEG C.
38. the crystal form as described in any one of claim 32-37 has heat substantially as shown in Figure 11 Gravimetric analysis figure.
39. the crystal form as described in any one of claim 32-38, when its experience is relatively wet from about 0% to about 95% When the relative humidity of degree increases, about 3.4% quality increase is shown.
40. the crystal form as described in any one of claim 32-39 is shown substantially as shown in Figure 12 Gravimetric analysis vapour system figure.
41. the crystal form as described in any one of claim 32-40, wherein the form contains not less than about 90 weights Measure %, not less than about 95 weight %, not less than about 98 weight %, not less than about 99 weight % or the knot not less than 99.5 weight % Crystalline form IV.
42. the crystal form V of the compound of Formulas I：
43. crystal form as claimed in claim 42 has and is included in about 6.7,7.9,10.7,12.8,17.1 and 23.7 Spend the X-ray powder diffraction figure sample at one or more peaks at ± 0.2 θ of 2- θ.
44. the crystal form as described in any one of claim 42 or 43 has substantially as shown in Figure 13 X-ray powder diffraction figure sample.
45. the crystal form as described in any one of claim 42-44, with differential scanning calorimetry thermogram, The differential scanning calorimetry thermogram includes the endothermic event with about 113 DEG C and about 181 DEG C of temperature.
46. the crystal form as described in any one of claim 42-45, it is substantially poor as shown in Figure 14 to have Show scanning calorimetry thermogram.
47. the crystal form as described in any one of claim 42-46, have comprising when being heated to about from about 25 DEG C The thermogravimetry figure of about 4.1% mass loss at 140 DEG C.
48. the crystal form as described in any one of claim 42-47 has substantially hot as shown in Figure 14 Gravimetric analysis figure.
49. the crystal form as described in any one of claim 42-48, when its experience is relatively wet from about 0% to about 95% When the relative humidity of degree increases, about 1% quality increase is shown.
50. the crystal form as described in any one of claim 42-49 is shown substantially as shown in Figure 15 Gravimetric analysis vapour system figure.
51. the crystal form as described in any one of claim 42-50, wherein the form contains not less than about 90 weights Measure %, not less than about 95 weight %, not less than about 98 weight %, not less than about 99 weight % or the knot not less than 99.5 weight % Crystalline form V.
52. the crystalline Formula IV of the compound of Formulas I：
53. crystal form as claimed in claim 52 has and is included in about 6.8,8.0,16.3 and 17.5 degree of ± 0.2 θ of 2- θ The X-ray powder diffraction figure sample at one or more peaks at place.
54. the crystal form as described in any one of claim 52 or 53 has substantially as shown in Figure 16 X-ray powder diffraction figure sample.
55. the crystal form as described in any one of claim 52-54, with differential scanning calorimetry thermogram, The differential scanning calorimetry thermogram includes the endothermic event with about 175 DEG C and about 238 DEG C of temperature.
56. the crystal form as described in any one of claim 52-55 has difference substantially as shown in Figure 17 Show scanning calorimetry thermogram.
57. the crystal form as described in any one of claim 52-56, have comprising when being heated to about from about 25 DEG C The thermogravimetry figure of about 1% mass loss at 140 DEG C.
58. the crystal form as described in any one of claim 52-57 has heat substantially as shown in Figure 17 Gravimetric analysis figure.
59. the crystal form as described in any one of claim 52-58, when its experience is relatively wet from about 40% to about 80% When the relative humidity of degree increases, about 0.5% quality increase is shown.
60. the crystal form as described in any one of claim 52-59, when its experience is relatively wet from about 0% to about 90% When the relative humidity of degree increases, about 3.1% quality increase is shown.
61. the crystal form as described in any one of claim 52-60 is shown substantially as shown in Figure 18 Gravimetric analysis vapour system figure.
62. the crystal form as described in any one of claim 52-61, wherein the form contains not less than about 90 weights Measure %, not less than about 95 weight %, not less than about 98 weight %, not less than about 99 weight % or the knot not less than 99.5 weight % Crystalline form VI.
63. mixture is selected from the crystallization of the form described in claim 1,14,24,32,42 and 52 it includes two or more Form.
64. unbodied：
65. the crystal form I of the compound of Formula II：
66. the crystal form as described in claim 65 has and is included at about 7.2,9.2 and 18.0 degree of ± 0.2 θ of 2- θ The X-ray powder diffraction figure sample at one or more peaks.
67. the crystal form as described in any one of claim 65 or 66 has substantially as shown in Figure 20 X-ray powder diffraction figure sample.
68. the crystal form as described in any one of claim 65-67, with differential scanning calorimetry thermogram, The differential scanning calorimetry thermogram includes the heat absorption thing with about 240 DEG C of start temperature and the peak at about 250 DEG C Part.
69. the crystal form as described in any one of claim 65-68 has difference substantially as shown in Figure 21 Show scanning calorimetry thermogram.
70. the crystal form as described in any one of claim 65-69 has heat substantially as shown in Figure 21 Gravimetric analysis figure.
71. the crystal form as described in any one of claim 65-70, when its experience is relatively wet from about 0% to about 90% When the relative humidity of degree increases, about 14% quality increase is shown.
72. the crystal form as described in any one of claim 65-71 is shown substantially as shown in Figure 22 Gravimetric analysis vapour system figure.
73. the crystal form as described in any one of claim 65-72, wherein the form contains not less than about 90 weights Measure %, not less than about 95 weight %, not less than about 98 weight %, not less than about 99 weight % or the formula not less than 99.5 weight % The crystal form I of II.
74. the crystalline Formula II of the compound of Formula II：
75. the crystal form as described in claim 74 has and is included at about 4.8,13.3 and 24.9 degree of ± 0.2 θ of 2- θ The X-ray powder diffraction figure sample at one or more peaks.
76. the crystal form as described in any one of claim 74 or 75 has substantially as shown in Figure 23 X-ray powder diffraction figure sample.
77. the crystal form as described in any one of claim 74-76, with differential scanning calorimetry thermogram, The differential scanning calorimetry thermogram includes the heat absorption thing with about 80 DEG C of start temperature and the peak at about 106 DEG C Part.
78. the crystal form as described in any one of claim 74-77 has difference substantially as shown in Figure 24 Show scanning calorimetry thermogram.
79. the crystal form as described in any one of claim 74-78, have comprising when being heated to about from about 25 DEG C The thermogravimetry figure of about 10% mass loss at 140 DEG C.
80. the crystal form as described in any one of claim 74-79 has heat substantially as shown in Figure 24 Gravimetric analysis figure.
81. the crystal form as described in any one of claim 74-80, when its experience is relatively wet from about 75% to about 0% When the relative humidity of degree declines, about 12% Mass lost is shown.
82. the crystal form as described in any one of claim 74-81 is shown substantially as shown in Figure 25 Gravimetric analysis vapour system figure.
83. the crystal form as described in any one of claim 74-82, wherein the form contains not less than about 90 weights Measure %, not less than about 95 weight %, not less than about 98 weight %, not less than about 99 weight % or the formula not less than 99.5 weight % The crystalline Formula II of II.
84. mixture is selected from the crystal form of the form described in claim 65 and 74 it includes two or more.
85. unbodied
86. pharmaceutical composition, it includes the crystal forms or claim 64 or 85 described in any one of claim 1-63 The amorphous form and pharmaceutically acceptable carrier.
87. the pharmaceutical composition as described in claim 86, wherein the composition is formulated for being administered orally.
88. the pharmaceutical composition as described in claim 86 or 87, wherein the composition is configured to single formulation.
89. the method for one or more symptoms for treating, preventing or improving hyperkinesia venereal disease disease, the method packet Include using the crystal form described in any one of claim 1-63 or the amorphous form described in claim 64 or 85 or Pharmaceutical composition described in claim 86-88.
90. the method as described in claim 89, wherein the hyperkinesia venereal disease disease is Huntington disease, tardive Obstacle, figure rett syndrome, dystonia, hemiballismus, chorea, senile chorea or twitch.
91. the method as described in claim 90, wherein the hyperkinesia venereal disease disease is Huntington disease.
92. the method as described in claim 90, wherein the hyperkinesia venereal disease disease is tardive dyskinesia.
93. the method as described in claim 90, wherein the hyperkinesia venereal disease disease is figure rett syndrome.
94. the method as described in claim 90, wherein the hyperkinesia venereal disease disease is twitch.
95. the method for inhibiting the vesicular monoamine transporters isoform 2 in individual, the method includes giving the individual to apply With the crystal form described in any one of claim 1-63 or the amorphous form described in claim 64 or 85 or right It is required that the pharmaceutical composition described in 86-88.
96. the nothing described in the crystal form or claim 64 or 85 that are used to prepare described in any one of claim 1-63 is fixed The method of shape form, the method includes so that the compound of Formulas I or Formula II is contacted with solvent.
97. the method as described in claim 96, wherein the solvent is selected from hydrocarbon, chlorohydrocarbon, alcohol, ether, ketone, ester, carbonic ester, acyl Amine, nitrile, nitro compound, heterocycle, water and its mixture.
98. the method as described in claim 97, wherein the solvent is selected from acetonitrile, 1,2- dichloroethanes, DMF ,-two Evil of Isosorbide-5-Nitrae Alkane, methanol, 2-methyl cellosolve, MIBK, toluene, heptane, cumene, acetone, n-butyl alcohol, MTBE, ethyl alcohol, ethyl acetate, formic acid Ethyl ester, isobutyl acetate, isopropyl acetate, methyl acetate, nitromethane, 1- propyl alcohol, IPA, MEK, THF, water and its mixing Object.
99. the nothing described in the crystal form or claim 64 or 85 that are used to prepare described in any one of claim 1-63 is fixed The method of shape form, the method includes following step：(a) slurry of the compound of formula I in a solvent at the first temperature Body；(b) crystal form or the amorphous form are generated by the way that the slurry is exposed to second temperature.
100. the method as described in claim 99, wherein generating the knot by the way that the solution is cooled to the second temperature Crystalline form or the amorphous form.
101. the nothing described in the crystal form or claim 64 or 85 that are used to prepare described in any one of claim 1-63 The method of amorphous form, the method includes following step：(a) compound of formula I is in a solvent at the first temperature Solution；(b) slurry is formed by the way that the solution is cooled to second temperature；(c) by being heated and being cooled down with one or more Slurry described in circular treatment generates the crystal form or the amorphous form.
102. the method as described in claim 101, wherein about -50 DEG C to about 120 DEG C, about -50 DEG C to about 100 DEG C, about -20 DEG C to about 80 DEG C, about 0 DEG C to about 80 DEG C, about 10 DEG C to about 80 DEG C, about 20 DEG C to about 80 DEG C, about 20 DEG C to about 60 DEG C or about 20 DEG C the heating and cooling cycle are carried out to about 50 DEG C of temperature range.
103. the method as described in any one of claim 99-102, wherein first temperature is about 20 DEG C to about 200 DEG C, about 20 DEG C to about 150 DEG C, about 20 DEG C to about 100 DEG C or about 20 DEG C to about 80 DEG C.
104. the method as described in any one of claim 99-103, wherein the second temperature is about -100 DEG C to 100 DEG C, about -50 DEG C to about 50 DEG C, about -10 DEG C to about 30 DEG C, about 20 DEG C to about 200 DEG C, about 20 DEG C to about 150 DEG C or about 20 DEG C extremely About 100 DEG C.
105. the method as described in any one of claim 96-104, the method further include the separation crystal form or The step of amorphous form.
106. the method as described in any one of claim 96-105, wherein the solvent be selected from hydrocarbon, chlorohydrocarbon, alcohol, ether, Ketone, ester, carbonic ester, amide, nitrile, nitro compound, heterocycle, water and its mixture.
107. the method as described in any one of claim 96-106, wherein the solvent is selected from acetonitrile, 1,2-, bis- chloroethenes Alkane, DMF, 1,4- dioxane, methanol, 2-methyl cellosolve, MIBK, toluene, heptane, cumene, acetone, n-butyl alcohol, MTBE, second Alcohol, ethyl acetate, Ethyl formate, isobutyl acetate, isopropyl acetate, methyl acetate, nitromethane, 1- propyl alcohol, IPA, MEK, THF, water and its mixture.
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